Aryl substituted oxazolidinones with antibacterial activity

ABSTRACT

Compounds of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof,  
                 
wherein, for example, HET is an N-linked 5-membered, fully or partially unsaturated heterocyclic ring, or HET is an N-linked 6-membered di-hydro-heteroaryl ring; 
 
Q is, for example, Q1 or Q2:  
                 
      wherein R 2  and R 3  are independently hydrogen or fluoro; 
 
T is, for example, (TAa1) or (TAa2):  
                 
    wherein R 4h  and R 5h  are independently selected, for example, from hydrogen, halo, trifluoromethyl, cyano, nitro and (1-4C)alkoxy; are useful as antibacterial agents; and processes for their manufacture and pharmaceutical compositions containing them are described.

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB02/04796, filed Oct. 23, 2002, whichclaims priority from Provisional Application No. 60/330,589, filed Oct.25, 2001, the specification of which is incorporated by referenceherein. International Application No. PCT/GB02/04796 was published underPCT Article 21(2) in English.

The present invention relates to antibiotic compounds and in particularto antibiotic compounds containing a substituted oxazolidinone ring.This invention further relates to processes for their preparation, tointermediates useful in their preparation, to their use as therapeuticagents and to pharmaceutical compositions containing them.

The international microbiological community continues to express seriousconcern that the evolution of antibiotic resistance could result instrains against which currently available antibacterial agents will beineffective. In general, bacterial pathogens may be classified as eitherGram-positive or Gram-negative pathogens. Antibiotic compounds witheffective activity against both Gram-positive and Gram-negativepathogens are generally regarded as having a broad spectrum of activity.The compounds of the present invention are regarded as effective againstboth Gram-positive and certain Gram-negative pathogens.

Gram-positive pathogens, for example Staphylococci, Enterococci, andStreptococci are particularly important because of the development ofresistant strains which are both difficult to treat and difficult toeradicate from the hospital environment once established. Examples ofsuch strains are methicillin resistant staphylococcus (MRSA),methicillin resistant coagulase negative staphylococci (MRCNS),penicillin resistant Streptococcus pneumoniae and multiply resistantEnterococcus faecium.

The major clinically effective antibiotic for treatment of suchresistant Gram-positive pathogens is vancomycin. Vancomycin is aglycopeptide and is associated with nephrotoxicity and ototoxicity.Furthermore, and most importantly, antibacterial resistance tovancomycin and other glycopeptides is also appearing. This resistance isincreasing at a steady rate rendering these agents less and lesseffective in the treatment of Gram-positive pathogens. There is also nowincreasing resistance appearing towards agents such as β-lactams,quinolones and macrolides used for the treatment of upper respiratorytract infections, also caused by certain Gram negative strains includingH. influenzae and M. catarrhalis.

Certain antibacterial compounds containing an oxazolidinone ring havebeen described in the art (for example, Walter A. Gregory et al in J.Med. Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J. Med. Chem.1992, 35, 1156-1165). Such antibacterial oxazolidinone compounds with a5-acetamidomethyl sidechain may be subject to mammalian peptidasemetabolism. Furthermore, bacterial resistance to known antibacterialagents may develop, for example, by (i) the evolution of active bindingsites in the bacteria rendering a previously active pharmacophore lesseffective or redundant, (ii) the evolution of means to chemicallydeactivate a given pharmacophore and/or (iii) the development and/orup-regulation of efflux mechanisms. Therefore, there remains an ongoingneed to find new antibacterial agents with a favourable pharmacologicalprofile, in particular for compounds containing new pharmacophores.

We have discovered a new class of antibiotic compounds containing anaryl substituted oxazolidinone ring in which the aryl ring is itselffurther substituted. These compounds have useful activity againstGram-positive pathogens including MRSA and MRCNS and, in particular,against various strains exhibiting resistance to vancomycin and againstE. faecium strains resistant to both aminoglycosides and clinically usedβ-lactams, but also to fastidious Gram negative strains such as H.influenzae, M. catarrhalis, mycoplasma spp. and chlamydial strains.

Accordingly the present invention provides a compound of the formula(I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysableester thereof,

wherein

-   HET is an N-linked 5-membered, fully or partially unsaturated    heterocyclic ring, containing either (i) 1 to 3 further nitrogen    heteroatoms or (ii) a further heteroatom selected from O and S    together with an optional further nitrogen heteroatom; which ring is    optionally substituted on a C atom, other than a C atom adjacent to    the linking N atom, by an oxo or thioxo group; and/or which ring is    optionally substituted on any available C atom, other than a C atom    adjacent to the linking N atom, by a substituent Rs wherein;-   Rs is selected from the group:-   (Rsa): halogen, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkenyl,    (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, amino,    (1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkenylamino,    (1-4C)alkylcarbonylamino, (1-4C)alkylthiocarbonylamino,    (1-4C)alkyl-OCO—NH—, (1-4C)alkyl-NH—CO—NH—, (1-4C)alkyl-NH—CS—NH—,    (1-4C)alkyl-SO₂—NH— or (1-4C)alkyl-S(O)q- (wherein q is 0, 1 or 2);-   or Rs is selected from the group-   (Rsb): (1-4C)alkyl group which is optionally substituted by one    substituent selected from hydroxy, (1-4C)alkoxy, amino, cyano,    azido, (2-4C)alkenyloxy, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl,    (1-4C)alkylamino, (2-4C)alkenylamino, (1-4C)alkyl-SO₂—NH—,    (1-4C)alkylcarbonylamino, (1-4C)alkylthiocarbonylamino,    (1-4C)alkyl-OCO—NH—, (1-4C)alkyl-NH—CO—NH—, (1-4C)alkyl-NH—CS—NH—,    (1-4C)alkyl-SO₂—NH—, (1-4C)alkyl-S(O)q- (wherein q is 0, 1 or 2),    (3-6C)cycloalkyl, (3-6C)cycloalkenyl, or an N-linked 5-membered    heteroaryl ring, which ring contains either (i) 1 to 3 further    nitrogen heteroatoms or (ii) a further heteroatom selected from O    and S together with an optional further nitrogen heteroatom; which    ring is optionally substituted on a carbon atom by an oxo or thioxo    group; and/or the ring is optionally substituted on a carbon atom by    1 or 2 (1-4C)alkyl groups; and/or on an available nitrogen atom    (provided that the ring is not thereby quaternised) by (1-4C)alkyl;-   or Rs is selected from a group of formula (Rsc1) to (Rsc3):-   (Rsc1): a fully saturated 4-membered monocyclic ring containing 1 or    2 heteroatoms independently selected from O, N and S (optionally    oxidised), and linked via a ring nitrogen or carbon atom; or-   (Rsc2): a saturated or unsaturated 5-membered monocyclic ring    containing 1 heteroatom selected from O, N and S (optionally    oxidised), and linked via a ring nitrogen atom if the ring is not    thereby quaternised, or a ring carbon atom; or-   (Rsc3): a saturated or unsaturated 6- to 8-membered monocyclic ring    containing 1 or 2 heteroatoms independently selected from O, N and S    (optionally oxidised), and linked via a ring nitrogen atom if the    ring is not thereby quaternised, or a ring carbon atom;-   wherein said rings in (Rsc1) to (Rsc3) are optionally substituted on    an available carbon atom by 1 or 2 substituents independently    selected from hydroxy, (1-4C)alkoxy, amino, cyano, azido,    (2-4C)alkenyloxy, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl,    (1-4C)alkylamino, (2-4C)alkenylamino, (1-4C)alkyl-SO₂—NH—,    (1-4C)alkylcarbonylamino, (1-4C)alkylthiocarbonylamino,    (1-4C)alkyl-OCO—NH—, (1-4C)alkyl-NH—CO—NH—, (1-4C)alkyl-NH—CS—NH—,    (1-4C)alkyl-SO₂—NH—, (1-4C)alkyl-S(O)q- (wherein q is 0, 1 or 2),    (3-6C)cycloalkyl or (3-6C)cycloalkenyl;-   or Rs is selected from the group-   (Rsd): cyano, nitro, azido, formyl, (1-4C)alkylcarbonyl or    (1-4C)alkoxycarbonyl; and wherein at each occurrence of an Rs    substituent containing an alkyl, alkenyl, alkynyl, cycloalkyl or    cycloalkenyl moiety in (Rsa), (Rsb) or (Rsc1) to (Rsc3) each such    moiety is optionally further substituted on an available carbon atom    with one or more substituents independently selected from F, Cl and    Br and/or by one cyano group;-   and/or which ring is optionally substituted on an available nitrogen    atom (provided that the ring is not thereby quaternised) by    (1-4C)alkyl; or-   HET is an N-linked 6-membered di-hydro-heteroaryl ring containing up    to three nitrogen heteroatoms in total (including the linking    heteroatom), which ring is substituted on a suitable C atom, other    than a C atom adjacent to the linking N atom, by oxo or thioxo    and/or which ring is optionally substituted on any available C atom,    other than a C atom adjacent to the linking N atom, by one or two    substituents Rs, wherein Rs is as hereinbefore defined, and/or on an    available nitrogen atom (provided that the ring is not thereby    quaternised) by (1-4C)alkyl; and wherein at each occurrence of    alkyl, alkenyl and cycloalkyl HET substituents, each is optionally    substituted with one or more substituents independently selected    from F, Cl and Br and/or by one cyano group:-   Q is selected from Q1 to Q10-    wherein R² and R³ are independently hydrogen or fluoro;-   wherein A₁ is carbon or nitrogen; B₁ is O or S (or, in Q9 only, NH);    X_(q) is O, S or N—R¹ (wherein R¹ is hydrogen, (1-4C)alkyl or    hydroxy-(1-4C)alkyl); and wherein in Q7 each A₁ is independently    selected from carbon or nitrogen, with a maximum of 2 nitrogen    heteroatoms in the 6-membered ring, and Q7 is linked to T via any of    the A₁ atoms (when A₁ is carbon), and linked in the 5-membered ring    via the specified carbon atom, or via A₁ when A₁ is carbon; Q8 and    Q10 are linked to T via either of the specified carbon atoms in the    5-membered ring, and linked in the benzo-ring via either of the two    specified carbon atoms on either side of the linking bond shown; and    Q9 is linked via either of the two specified carbon atoms on either    side of the linking bond shown;-   T is an optionally substituted C-linked (fully unsaturated)    5-membered heteroaryl ring system containing 1, 2 or 3 heteroatoms    drawn in combination from O, N, or S, optionally substituted, by one    or more substituents independently selected from R^(4h), R^(5h) and    R^(6h) defined hereinafter;-   T is preferably selected from the following groups of formula (TAa1)    to (TAa6) below (wherein AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4,    AR4a, CY1 and CY2 are defined hereinbelow);-    wherein:-   R^(6h) is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxycarbonyl,    (1-4C)alkanoyl, carbamoyl and cyano;-   R^(4h) and R^(5h) are independently selected from hydrogen, halo,    trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O)_(q)— (q    is 0, 1 or 2), (1-4C)alkanoyl, (1-4C)alkoxycarbonyl,    benzyloxy-(1-4C)alkyl, (2-4C)alkanoylamino, —CONRcRv and —NRcRv    wherein any (1-4C)alkyl group contained in the preceding values for    R^(4h) and R^(5h) is optionally substituted by up to three    substituents independently selected from hydroxy (not on C1 of an    alkoxy group, and excluding geminal disubstitution), oxo,    trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (2-4C)alkanoyloxy,    hydroxyimino, (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)— (q is 0, 1 or    2), (1-4C)alkylSO₂—NRv-, (1-4C)alkoxycarbonyl, —CONRcRv, and —NRcRv    (not on C1 of an alkoxy group, and excluding geminal    disubstitution); wherein Rv is hydrogen or (1-4C)alkyl and Rc is as    hereinafter defined;-   R^(4h) and R^(5h) may further be independently selected from    (1-4C)alkyl {optionally substituted by up to three substituents    independently selected from hydroxy (excluding geminal    disubstitution), oxo, trifluoromethyl, cyano, nitro, (1-4C)alkoxy,    (2-4C)alkanoyloxy, hydroxyimino, (1-4C)alkoxyimino,    (1-4C)alkylS(O)_(q)— (q is 0, 1 or 2), (1-4C)alkylSO₂—NRv-,    (1-4C)alkoxycarbonyl, —CONRcRv, and —NRcRv (excluding geminal    disubstitution); wherein Rv is hydrogen or (1-4C)alkyl}; Rc is as    hereinafter defined; and wherein-   any (1-4C)alkyl group contained in the immediately preceding    optional substituents (when R^(4h) and R^(5h) are independently    (1-4C)alkyl) is itself optionally substituted by up to three    substituents independently selected from hydroxy (not on C1 of an    alkoxy group, and excluding geminal disubstitution), oxo,    trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (2-4C)alkanoyloxy,    hydroxyimino, (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)— (q is 0, 1 or    2), (1-4C)alkylSO₂—NRv-, (1-4C)alkoxycarbonyl, —CONRcRv, and —NRcRv    (not on C1 of an alkoxy group, and excluding geminal    disubstitution); wherein Rv is hydrogen or (1-4C)alkyl and Rc is as    hereinafter defined;-   or R^(4h) is selected from one of the groups in (TAaa) to (TAac)    below, or (where appropriate) one of R^(4h) and R^(5h) is selected    from the above list of R^(4h) and R^(5h) values, and the other is    selected from one of the groups in (TAaa) to (TAac) below:-   (TAaa) a group of the formula (TAaa1)-    wherein Z⁰ is hydrogen or (1-4C)alkyl;-   X⁰ and Y⁰ are independently selected from hydrogen, (1-4C)alkyl,    (1-4C)alkoxycarbonyl, halo, cyano, nitro, (1-4C)alkylS(O)_(q)— (q is    0, 1 or 2), RvRwNSO₂—, trifluoromethyl, pentafluoroethyl,    (1-4C)alkanoyl and —CONRvRw [wherein Rv is hydrogen or (1-4C)alkyl;    Rw is hydrogen or (1-4C)alkyl]; or-   one of X⁰ and Y⁰ is selected from the above list of X⁰ and Y⁰    values, and the other is selected from phenyl, phenylcarbonyl,    —S(O)_(q)-phenyl (q is 0, 1 or 2), N-(phenyl)carbamoyl,    phenylaminosulfonyl, AR2, (AR2)-CO—, (AR2)-S(O)q- (q is 0, 1 or 2),    N-(AR2)carbamoyl and (AR2)aminosulfonyl; wherein any phenyl group in    (TAaa) may be optionally substituted by up to three substituents    independently selected from (1-4C)alkyl, cyano, trifluoromethyl,    nitro, halo and (1-4C)alkylsulfonyl;-   (TAab) an acetylene of the formula —≡—H or —≡-(1-4C)alkyl;-   (TAac) —X¹—Y¹-AR2, —X¹—Y¹-AR2a, —X¹—Y¹-AR2b, —X¹—Y¹-AR3, —X¹—Y¹-AR3a    or —X¹—Y¹-AR3b;-   wherein X¹ is a direct bond or —CH(OH)— and-   Y¹ is —(CH₂)_(m)—, —(CH₂)_(n)—NH—(CH₂)_(m)—, —CO—(CH₂)_(m)—,    —CONH—(CH₂)_(m)—, —C(═S)NH—(CH₂)_(m)— or —C(═O)O—(CH₂)_(m)—;-   or wherein X¹ is —(CH₂)_(n)— or —CH(Me)-(CH₂)_(m)— and Y¹ is    —(CH₂)_(m)—NH—(CH₂)_(m)—, —CO—(CH₂)_(m)—, —CONH—(CH₂)_(m)—,    —C(═S)NH—(CH₂)_(m)—, —C(═O)O—(CH₂)_(m)— or —S(O)_(q)—(CH₂)_(m)—;-   or wherein X¹ is —CH₂O—, —CH₂NH— or —CH₂N((1-4C)alkyl)- and Y¹ is    —CO—(CH₂)_(m)—, —CONH—(CH₂)_(m)— or —C(═S)NH—(CH₂)_(m)—; and    additionally Y¹ is —SO₂— when X¹ is —CH₂NH— or —CH₂N((1-4C)alkyl)-,    and Y¹ is —(CH₂)_(m)— when X¹ is —CH₂O— or —CH₂N((1-4C)alkyl)-;    wherein n is 1, 2 or 3; m is 0, 1, 2 or 3 and q is 0, 1 or 2; and    when Y¹ is —(CH₂)_(m)—NH—(CH₂)_(m)— each m is independently selected    from 0, 1, 2 or 3;-   wherein Rc is selected from groups (Rc1) to (Rc5):-   (Rc1) (1-6C)alkyl {optionally substituted by one or more    (1-4C)alkanoyl groups (including geminal disubstitution) and/or    optionally monosubstituted by cyano, (1-4C)alkoxy, trifluoromethyl,    (1-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR1    defined hereinafter), (1-4C)alkylS(O)_(q)— (q is 0, 1 or 2); or, on    any but the first carbon atom of the (1-6C)alkyl chain, optionally    substituted by one or more groups (including geminal disubstitution)    each independently selected from hydroxy and fluoro, and/or    optionally monosubstituted by oxo, —NRvRw [wherein Rv is hydrogen or    (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], (1-6C)alkanoylamino,    (1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino,    (1-4C)alkylS(O)_(p)NH— or (1-4C)alkylS(O)_(p)-((1-4C)alkyl)N— (p is    1 or 2)};-   (Rc2) R¹³CO—, R¹³SO₂— or R¹³CS—-   wherein R¹³ is selected from (Rc2a) to (Rc2e):-   (Rc2a) AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;-   (Rc2b) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, —NRvRw    [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or    (1-4C)alkyl], ethenyl, 2-(1-4C)alkylethenyl, 2-cyanoethenyl,    2-cyano-2-((1-4C)alkyl)ethenyl, 2-nitroethenyl,    2-nitro-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl,    2-((1-4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl,    2-(AR2a)ethenyl;-   (Rc2c) (1-10C)alkyl {optionally substituted by one or more groups    (including geminal disubstitution) each independently selected from    hydroxy, (1-10C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy,    (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, carboxy,    phosphoryl [—O—P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivatives    thereof], phosphiryl [—O—P(OH)₂ and mono- and di-(1-4C)alkoxy    derivatives thereof], and amino; and/or optionally substituted by    one group selected from phosphonate [phosphono, —P(O)(OH)₂, and    mono- and di-(1-4C)alkoxy derivatives thereof], phosphinate [—P(OH)₂    and mono- and di-(1-4C)alkoxy derivatives thereof], cyano, halo,    trifluoromethyl, (1-4C)alkoxycarbonyl,    (1-4C)alkoxy-(1-4C)alkoxycarbonyl,    (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkylamino,    di((1-4C)alkyl)amino, (1-6C)alkanoylamino,    (1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino,    (1-4C)alkylaminocarbonyl, di((1-4C)alkyl)aminocarbonyl,    (1-4C)alkylS(O)_(p)NH—, (1-4C)alkylS(O)_(p)-((1-4C)alkyl)N—,    fluoro(1-4C)alkylS(O)_(p)NH—,    fluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)N—, (1-4C)alkylS(O)_(q)— [the    (1-4C)alkyl group of (1-4C)alkylS(O)_(q)— being optionally    substituted by one substituent selected from hydroxy, (1-4C)alkoxy,    (1-4C)alkanoyl, phosphoryl [—O—P(O)(OH)₂, and mono- and    di-(1-4C)alkoxy derivatives thereof], phosphiryl [—O—P(OH)₂ and    mono- and di-(1-4C)alkoxy derivatives thereof], amino, cyano, halo,    trifluoromethyl, (1-4C)alkoxycarbonyl,    (1-4C)alkoxy-(1-4C)alkoxycarbonyl,    (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, carboxy,    (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino,    (1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino,    (1-4C)alkylaminocarbonyl, di((1-4C)alkyl)aminocarbonyl,    (1-4C)alkylS(O)_(p)NH—, (1-4C)alkylS(O)_(p)-((1-4C)alkyl)N—,    (1-4C)alkylS(O)_(q)—, AR1-S(O)_(q)—, AR2-S(O)_(q)—, AR3-S(O)_(q)—    and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3    containing groups], CY1, CY2, AR1, AR2, AR3, AR1-O—, AR2-O—, AR3-O—,    AR1-S(O)_(q)—, AR2-S(O)_(q)—, AR3-S(O)_(q)—, AR1-NH—, AR2-NH—,    AR3-NH— (p is 1 or 2 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a    and AR3b versions of AR2 and AR3 containing groups};-   (Rc2d) R¹⁴C(O)O(1-6C)alkyl wherein R¹⁴ is AR1, AR2, (1-4C)alkylamino    (the (1-4C)alkyl group being optionally substituted by    (1-4C)alkoxycarbonyl or by carboxy), benzyloxy-(1-4C)alkyl or    (1-10C)alkyl {optionally substituted as defined for (Rc2c)};-   (Rc2e) R¹⁵O— wherein R¹⁵ is benzyl, (1-6C)alkyl {optionally    substituted as defined for (Rc2c)}, CY1, CY2 or AR2b;-   (Rc3) hydrogen, cyano, 2-cyanoethenyl,    2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl,    2-((1-4C)alkoxycarbonyl)ethenyl, 2-nitroethenyl,    2-nitro-2-((1-4C)alkyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or    of the formula-   (Rc3a)-    wherein X⁰⁰ is —OR¹⁷, —SR¹⁷, —NHR¹⁷ and —N(R¹⁷)₂;-   wherein R¹⁷ is hydrogen (when X⁰⁰ is —NHR¹⁷ and —N(R¹⁷)₂), and R¹⁷    is (1-4C)alkyl, phenyl or AR2 (when X⁰⁰ is —OR¹⁷, —SR¹⁷ and —NHR¹⁷);    and R¹⁶ is cyano, nitro, (1-4C)alkylsulfonyl,    (4-7C)cycloalkylsulfonyl, phenylsulfonyl, (1-4C)alkanoyl and    (1-4C)alkoxycarbonyl;-   (Rc4) trityl, AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b;-   (Rc5) RdOC(Re)=CH(C═O)—, RfC(═O)C(═O)—, RgN═C(Rh)C(═O)— or    RiNHC(Rj)=CHC(═O)— wherein Rd is (1-6C)alkyl; Re is hydrogen or    (1-6C)alkyl, or Rd and Re together form a (3-4C)alkylene chain; Rf    is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl,    (1-6C)alkoxy(1-6C)alkyl, —NRvRw [wherein Rv is hydrogen or    (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], (1-6C)alkoxy,    (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy,    (1-4C)alkylamino(2-6C)alkoxy, di-(1-4C)alkylamino(2-6C)alkoxy; Rg is    (1-6C)alkyl, hydroxy or (1-6C)alkoxy; Rh is hydrogen or (1-6C)alkyl;    Ri is hydrogen, (1-6C)alkyl, AR1, AR2, AR2a, AR2b and Rj is hydrogen    or (1-6C)alkyl; wherein-   AR1 is an optionally substituted phenyl or optionally substituted    naphthyl;-   AR2 is an optionally substituted 5- or 6-membered, fully unsaturated    (i.e with the maximum degree of unsaturation) monocyclic heteroaryl    ring containing up to four heteroatoms independently selected from    O, N and S (but not containing any O—O, O—S or S—S bonds), and    linked via a ring carbon atom, or a ring nitrogen atom if the ring    is not thereby quaternised;-   AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systems    retaining some, but not the full, degree of unsaturation), linked    via a ring carbon atom or linked via a ring nitrogen atom if the    ring is not thereby quaternised;-   AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having    no unsaturation), linked via a ring carbon atom or linked via a ring    nitrogen atom;

AR3 is an optionally substituted 8-, 9- or 10-membered, fullyunsaturated (i.e with the maximum degree of unsaturation) bicyclicheteroaryl ring containing up to four heteroatoms independently selectedfrom O, N and S (but not containing any O—O, O—S or S—S bonds), andlinked via a ring carbon atom in either of the rings comprising thebicyclic system;

-   AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systems    retaining some, but not the full, degree of unsaturation), linked    via a ring carbon atom, or linked via a ring nitrogen atom if the    ring is not thereby quaternised, in either of the rings comprising    the bicyclic system;-   AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having    no unsaturation), linked via a ring carbon atom, or linked via a    ring nitrogen atom, in either of the rings comprising the bicyclic    system;-   AR4 is an optionally substituted 13- or 14-membered, fully    unsaturated (i.e with the maximum degree of unsaturation) tricyclic    heteroaryl ring containing up to four heteroatoms independently    selected from O, N and S (but not containing any O—O, O—S or S—S    bonds), and linked via a ring carbon atom in any of the rings    comprising the tricyclic system;-   AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systems    retaining some, but not the full, degree of unsaturation), linked    via a ring carbon atom, or linked via a ring nitrogen atom if the    ring is not thereby quaternised, in any of the rings comprising the    tricyclic system;-   CY1 is an optionally substituted cyclobutyl, cyclopentyl or    cyclohexyl ring;-   CY2 is an optionally substituted cyclopentenyl or cyclohexenyl ring.

In another embodiment, the present invention provides a compound of theformula (I) as hereinbefore described, or a pharmaceutically-acceptablesalt, or an in-vivo hydrolysable ester thereof, wherein:

-   HET is an N-linked 5-membered, fully or partially unsaturated    heterocyclic ring, containing either (i) 1 to 3 further nitrogen    heteroatoms or (ii) a further heteroatom selected from O and S    together with an optional further nitrogen heteroatom; which ring is    optionally substituted on a C atom, other than a C atom adjacent to    the linking N atom, by an oxo or thioxo group; and/or which ring is    optionally substituted on any available C atom, other than a C atom    adjacent to the linking N atom, by a substituent selected from    (1-4C)alkyl, (2-4C)alkenyl, (3-6C)cycloalkyl, amino,    (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio,    (1-4C)alkoxy, (1-4C)alkoxycarbonyl, halogen, cyano and    trifluoromethyl and/or on an available nitrogen atom (provided that    the ring is not thereby quaternised) by (1-4C)alkyl; or-   HET is an N-linked 6-membered di-hydro-heteroaryl ring containing up    to three nitrogen heteroatoms in total (including the linking    heteroatom), which ring is substituted on a suitable C atom, other    than a C atom adjacent to the linking N atom, by oxo or thioxo    and/or which ring is optionally substituted on any available C atom,    other than a C atom adjacent to the linking N atom, by one or two    substituents independently selected from (1-4C)alkyl, (2-4C)alkenyl,    (3-6C)cycloalkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino,    (1-4C)alkylthio, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, halogen, cyano    and trifluoromethyl and/or on an available nitrogen atom (provided    that the ring is not thereby quaternised) by (1-4C)alkyl; and    wherein at each occurrence of alkyl, alkenyl and cycloalkyl HET    substituents, each is optionally substituted with one or more F, Cl    or CN.    -   In this specification, HET as an N-linked 5-membered ring may be        a fully or partially unsaturated heterocyclic ring, provided        there is some degree of unsaturation in the ring.    -   Particular examples of N-linked 5-membered heteroaryl rings        containing 2 to 4 heteroatoms independently selected from N, O        and S (with no O—O, O—S or S—S bonds) are preferably rings        containing 2 to 4 N atoms, in particular pyrazole, imidazole,        1,2,3-triazole (preferably 1,2,3-triazol-1-yl), 1,2,4-triazole        (preferably 1,2,4-triazol-1-yl) and tetrazole (preferably        tetrazol-2-yl).    -   Particular examples of N-linked 6-membered di-hydro-heteroaryl        rings containing up to three nitrogen heteroatoms in total        (including the linking heteroatom) include di-hydro versions of        pyrimidine, pyridazine, pyrazine, 1,2,3-triazine,        1,2,4-triazine, 1,3,5-triazine and pyridine.

It is to be understood that when a value for —X¹— is a two-atom link andis written, for example, as —CH₂NH— it is the left hand part (—CH₂—here) which is bonded to the group of formula (TAa1) to (TAa6) and theright hand part (—NH— here) which is bonded to —Y¹— in the definition in(TAac). Similarly, when —Y¹— is a two-atom link and is written, forexample, as —CONH— it is the left hand part of —Y¹— (—CO— here) which isbonded to the right hand part of —X¹—, and the right hand part of —Y¹—(—NH— here) which is bonded to the AR2, AR2a, AR2b, AR3, AR3a or AR3bmoiety in the definition in (TAac).

In this specification the term ‘alkyl’ includes straight chained andbranched structures. For example, (1-6C)alkyl includes propyl, isopropyland tert-butyl. However, references to individual alkyl groups such as“propyl” are specific for the straight chained version only, andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. A similar conventionapplies to other radicals, for example halo(1-4C)alkyl includes1-bromoethyl and 2-bromoethyl.

There follow particular and suitable values for certain substituents andgroups referred to in this specification. These values may be used whereappropriate with any of the definitions and embodiments disclosedhereinbefore, or hereinafter.

Examples of (1-4C)alkyl and (1-5C)alkyl include methyl, ethyl, propyl,isopropyl and t-butyl; examples of (1-6C)alkyl include methyl, ethyl,propyl, isopropyl, t-butyl, pentyl and hexyl; examples of (1-10C)alkylinclude methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyland nonyl; examples of (1-4C)alkanoylamino-(1-4C)alkyl includeformamidomethyl, acetamidomethyl and acetamidoethyl; examples ofhydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl include hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of(1-4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl andpropoxycarbonyl; examples of 2-((1-4C)alkoxycarbonyl)ethenyl include2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of2-cyano-2-((1-4C)alkyl)ethenyl include 2-cyano-2-methylethenyl and2-cyano-2-ethylethenyl; examples of 2-nitro-2-((1-4C)alkyl)ethenylinclude 2-nitro-2-methylethenyl and 2-nitro-2-ethylethenyl; examples of2-((1-4C)alkylaminocarbonyl)ethenyl include2-(methylaminocarbonyl)ethenyl and 2-(ethylaminocarbonyl)ethenyl;examples of (2-4C)alkenyl include allyl and vinyl; examples of(2-4C)alkynyl include ethynyl and 2-propynyl; examples of (1-4C)alkanoylinclude formyl, acetyl and propionyl; examples of (1-4C)alkoxy includemethoxy, ethoxy and propoxy; examples of (1-6C)alkoxy and (1-10C)alkoxyinclude methoxy, ethoxy, propoxy and pentoxy; examples of(1-4C)alkylthio include methylthio and ethylthio; examples of(1-4C)alkylamino include methylamino, ethylamino and propylamino;examples of di-((1-4C)alkyl)amino include dimethylamino,N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino anddipropylamino; examples of halo groups include fluoro, chloro and bromo;examples of (1-4C)alkylsulfonyl include methylsulfonyl andethylsulfonyl; examples of (1-4C)alkoxy-(1-4C)alkoxy and(1-6C)alkoxy-(1-6C)alkoxy include methoxymethoxy, 2-methoxyethoxy,2-ethoxyethoxy and 3-methoxypropoxy; examples of(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include 2-(methoxymethoxy)ethoxy,2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and2-(2-ethoxyethoxy)ethoxy; examples of (1-4C)alkylS(O)₂amino includemethylsulfonylamino and ethylsulfonylamino; examples of(1-4C)alkanoylamino and (1-6C)alkanoylamino include formamido, acetamidoand propionylamino; examples of (1-4C)alkoxycarbonylamino includemethoxycarbonylamino and ethoxycarbonylamino; examples ofN-(1-4C)alkyl-N-(1-6C)alkanoylamino include N-methylacetamido,N-ethylacetamido and N-methylpropionamido; examples of(1-4C)alkylthiocarbonylamino include MeS—C(═O)—N— and EtS—C(═O)—N—;examples of (1-4C)alkylS(O)_(p)NH— wherein p is 1 or 2 includemethylsulfinylamino, methylsulfonylamino, ethylsulfinylamino andethylsulfonylamino; examples of (1-4C)alkylS(O)_(p)((1-4C)alkyl)N—wherein p is 1 or 2 include methylsulfinylmethylamino,methylsulfonylmethylamino, 2-(ethylsulfinyl)ethylamino and2-(ethylsulfonyl)ethylamino; examples of fluoro(1-4C)alkylS(O)_(p)NH—wherein p is 1 or 2 include trifluoromethylsulfinylamino andtrifluoromethylsulfonylamino; examples offluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)NH— wherein p is 1 or 2 includetrifluoromethylsulfinylmethylamino andtrifluoromethylsulfonylmethylamino; examples of(1-4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl andethoxy(hydroxy)phosphoryl; examples of di-(1-4C)alkoxyphosphoryl includedi-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl;examples of (1-4C)alkylS(O)_(q)— wherein q is 0, 1 or 2 includemethylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl andethylsulfonyl; examples of phenylS(O)_(q) and naphthylS(O)_(q)— whereinq is 0, 1 or 2 are phenylthio, phenylsulfinyl, phenylsulfonyl andnaphthylthio, naphthylsulfinyl and naphthylsulfonyl respectively;examples of benzyloxy-(1-4C)alkyl include benzyloxymethyl andbenzyloxyethyl; examples of a (3-4C)alkylene chain are trimethylene ortetramethylene; examples of (1-6C)alkoxy-(1-6C)alkyl includemethoxymethyl, ethoxymethyl and 2-methoxyethyl; examples ofhydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy;examples of (1-4C)alkylamino-(2-6C)alkoxy include 2-methylaminoethoxyand 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxyinclude 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples ofphenyl(1-4C)alkyl include benzyl and phenethyl; examples of(1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl;examples of di((1-4C)alkyl)carbamoyl include di(methyl)carbamoyl anddi(ethyl)carbamoyl; examples of hydroxyimino(1-4C)alkyl includehydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl;examples of (1-4C)alkoxyimino-(1-4C)alkyl include methoxyiminomethyl,ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl;examples of halo(1-4C)alkyl include, halomethyl, 1-haloethyl,2-haloethyl, and 3-halopropyl; examples of nitro(1-4C)alkyl includenitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples ofamino(1-4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and3-aminopropyl; examples of cyano(1-4C)alkyl include cyanomethyl,1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of(1-4C)alkanesulfonamido include methanesulfonamido andethanesulfonamido; examples of (1-4C)alkylaminosulfonyl includemethylaminosulfonyl and ethylaminosulfonyl; and examples ofdi-(1-4C)alkylaminosulfonyl include dimethylaminosulfonyl,diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl; examples of(1-4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy andpropylsulfonyloxy; examples of (1-4C)alkanoyloxy include acetoxy;examples of (1-4C)alkylaminocarbonyl include methylaminocarbonyl andethylaminocarbonyl; examples of di((1-4C)alkyl)aminocarbonyl includedimethylaminocarbonyl and diethylaminocarbonyl; examples of(3-6C)cycloalkyl and (3-8C)cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl; examples of (4-7C)cycloalkyl includecyclobutyl, cyclopentyl and cyclohexyl; examples of (3-6C)cycloalkenylinclude cyclopentenyl and cyclohexenyl; examples ofdi(N-(1-4C)alkyl)aminomethylimino include dimethylaminomethylimino anddiethylaminomethylimino.

Particular values for AR2 include, for example, for those AR2 containingone heteroatom, furan, pyrrole, thiophene; for those AR2 containing oneto four N atoms, pyrazole, imidazole, pyridine, pyrimidine, pyrazine,pyridazine, 1,2,3- & 1,2,4-triazole and tetrazole; for those AR2containing one N and one O atom, oxazole, isoxazole and oxazine; forthose AR2 containing one N and one S atom, thiazole and isothiazole; forthose AR2 containing two N atoms and one S atom, 1,2,4- and1,3,4-thiadiazole.

Particular examples of AR2a include, for example, dihydropyrrole(especially 2,5-dihydropyrrol-4-yl) and tetrahydropyridine (especially1,2,5,6-tetrahydropyrid-4-yl).

Particular examples of AR2b include, for example, tetrahydrofuran,pyrrolidine, morpholine (preferably morpholino), thiomorpholine(preferably thiomorpholino), piperazine (preferably piperazino),imidazoline and piperidine, 1,3-dioxolan4-yl, 1,3-dioxan-4-yl,1,3-dioxan-5-yl and 1,4-dioxan-2-yl.

Particular values for AR3 include, for example, bicyclic benzo-fusedsystems containing a 5- or 6-membered heteroaryl ring containing onenitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen,sulfur and nitrogen. Specific examples of such ring systems include, forexample, indole, benzofuran, benzothiophene, benzimidazole,benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline,quinoxaline, quinazoline, phthalazine and cinnoline.

Other particular examples of AR3 include 5/5-, 5/6 and 6/6 bicyclic ringsystems containing heteroatoms in both of the rings. Specific examplesof such ring systems include, for example, purine and naphthyridine.

Further particular examples of AR3 include bicyclic heteroaryl ringsystems with at least one bridgehead nitrogen and optionally a further1-3 heteroatoms chosen from oxygen, sulfur and nitrogen. Specificexamples of such ring systems include, for example,3H-pyrrolo[1,2-a]pyrrole, pyrrolo[2,1-b]thiazole,1H-imidazo[1,2-a]pyrrole, 1H-imidazo[1,2-a]imidazole,1H,3H-pyrrolo[1,2-c]oxazole, 1H-imidazo[1,5-a]pyrrole,pyrrolo[1,2-b]isoxazole, imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole,indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrazine,pyrrolo[1,2-a]pyrimidine, pyrido[2,1-c]-s-triazole,s-triazole[1,5-a]pyridine, imidazo[1,2-c]pyrimidine,imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine,imidazo[1,5-a]pyrazine, imidazo[1,5-a]pyrimidine,imidazo[1,2-b]-pyridazine, s-triazolo[4,3-a]pyrimidine,imidazo[5,1-b]oxazole and imidazo[2,1-b]oxazole. Other specific examplesof such ring systems include, for example, [1H]-pyrrolo[2,1-c]oxazine,[3H]-oxazolo[3,4-a]pyridine, [6H]-pyrrolo[2,1-c]oxazine andpyrido[2,1-c][1,4]oxazine. Other specific examples of 5/5-bicyclic ringsystems are imidazooxazole or imidazothiazole, in particularimidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, imidazo[5,1-b]oxazole orimidazo[2,1-b]oxazole.

Particular examples of AR3a and AR3b include, for example, indoline,1,3,4,6,9,9a-hexahydropyrido[2,1c][1,4]oxazin-8-yl,1,2,3,5,8,8a-hexahydroimidazo[1,5a]pyridin-7-yl,1,5,8,8a-tetrahydrooxazolo[3,4a]pyridin-7-yl,1,5,6,7,8,8a-hexahydrooxazolo[3,4a]pyridin-7-yl,(7aS)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl,(7aS)[5H]-1,2,3,7a-tetrahydropyrrolo[1,2c]imidazol-6-yl,(7aR)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl,[3H,5H]-pyrrolo[1,2-c]oxazol-6-yl,[5H]-2,3-dihydropyrrolo[1,2-c]imidazol-6-yl,[3H,5H]-pyrrolo[1,2-c]thiazol-6-yl,[3H,5H]-1,7a-dihydropyrrolo[1,2-c]thiazol-6-yl,[5H]-pyrrolo[1,2-c]imidazol-6-yl,[1H]-3,4,8,8a-tetrahydropyrrolo[2,1-c]oxazin-7-yl,[3H]-1,5,8,8a-tetrahydrooxazolo [3,4-a]pyrid-7-yl,[3H]-5,8-dihydroxazolo[3,4-a]pyrid-7-yl and 5,8-dihydroimidazo[1,5-a]pyrid-7-yl.

Particular values for AR4 include, for example, pyrrolo[a]quinoline,2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline,1H-pyrrolo[1,2-a]benzimidazole, 9H-imidazo[1,2-a]indole,5H-imidazo[2,1-a]isoindole, 1H-imidazo[3,4-a]indole,imidazo[1,2-a]quinoline, imidazo[2,1-a]isoquinoline,imidazo[1,5-a]quinoline and imidazo[5,1-a]isoquinoline.

The nomenclature used is that found in, for example, “HeterocyclicCompounds (Systems with bridgehead nitrogen), W. L. Mosby (IntercsiencePublishers Inc., New York), 1961, Parts 1 and 2.

Where optional substituents are listed such substitution is preferablynot geminal disubstitution unless stated otherwise. If not statedelsewhere suitable optional substituents for a particular group arethose as stated for similar groups herein.

Suitable substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4,AR4a, CY1 and CY2 are (on an available carbon atom) up to threesubstituents independently selected from (1-4C)alkyl {optionallysubstituted by (preferably one) substituents selected independently fromhydroxy, trifluoromethyl, (1-4C)alkyl S(O)_(q)— (q is 0, 1 or 2) (thislast substituent preferably on AR1 only), (1-4C)alkoxy,(1-4C)alkoxycarbonyl, cyano, nitro,

(1-4C)alkanoylamino, —CONRvRw or —NRvRw}, trifluoromethyl, hydroxy,halo, nitro, cyano, thiol, (1-4C)alkoxy, (1-4C)alkanoyloxy,dimethylaminomethyleneaminocarbonyl, di(N-(1-4C)alkyl)aminomethylimino,carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, (1-4C)alkylSO₂amino,(2-4C)alkenyl {optionally substituted by carboxy or(1-4C)alkoxycarbonyl}, (2-4C)alkynyl, (1-4C)alkanoylamino, oxo (═O),thioxo (═S),

(1-4C)alkanoylamino {the (1-4C)alkanoyl group being optionallysubstituted by hydroxy}, (1-4C)alkyl S(O)_(q)— (q is 0, 1 or 2) {the(1-4C)alkyl group being optionally substituted by one or more groupsindependently selected from cyano, hydroxy and

(1-4C)alkoxy}, —CONRvRw or —NRvRw [wherein Rv is hydrogen or(1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl].

Further suitable substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b,AR4, AR4a, CY1 and CY2 (on an available carbon atom), and also on alkylgroups (unless indicated otherwise) are up to three substituentsindependently selected from trifluoromethoxy, benzoylamino, benzoyl,phenyl {optionally substituted by up to three substituents independentlyselected from halo, (1-4C)alkoxy or cyano}, furan, pyrrole, pyrazole,imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole,oxazole, isothiazole, thiazole, thiophene, hydroxyimino(1-4C)alkyl,(1-4C)alkoxyimino(1-4C)alkyl, halo-(1-4C)alkyl, (1-4C)alkanesulfonamido,—SO₂NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or(1-4C)alkyl].

Preferable optional substituents on Ar2b as 1,3-dioxolan4-yl,1,3-dioxan-4-yl, 1,3-dioxan-5-yl or 1,4-dioxan-2-yl are mono- ordisubstitution by substituents independently selected from (1-4C)alkyl(including geminal disubstitution), (1-4C)alkoxy, (1-4C)alkylthio,acetamido, (1-4C)alkanoyl, cyano, trifluoromethyl and phenyl].

Preferable optional substituents on CY1 & CY2 are mono- ordisubstitution by substituents independently selected from (1-4C)alkyl(including geminal disubstitution), hydroxy, (1-4C)alkoxy,(1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano, and trifluoromethyl.

Suitable substituents on AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and AR4aare (on an available nitrogen atom, where such substitution does notresult in quaternization) (1-4C)alkyl, (1-4C)alkanoyl {wherein the(1-4C)alkyl and (1-4C)alkanoyl groups are optionally substituted by(preferably one) substituents independently selected from cyano,hydroxy, nitro, trifluoromethyl, (1-4C)alkyl S(O)_(q)— (q is 0, 1 or 2),(1-4C)alkoxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoylamino, —CONRvRw or—NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or(1-4C)alkyl]}, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxycarbonyl or oxo(to form an N-oxide).

Suitable pharmaceutically-acceptable salts include acid addition saltssuch as methanesulfonate, fumarate, hydrochloride, citrate, maleate,tartrate and (less preferably) hydrobromide. Also suitable are saltsformed with phosphoric and sulfuric acid. In another aspect suitablesalts are base salts such as an alkali metal salt for example sodium, analkaline earth metal salt for example calcium or magnesium, an organicamine salt for example triethylamine, morpholine, N-methylpiperidine,N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine,tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such aslysine. There may be more than one cation or anion depending on thenumber of charged functions and the valency of the cations or anions. Apreferred pharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, saltswhich are less soluble in the chosen solvent may be preferred whetherpharmaceutically-acceptable or not.

The compounds of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). A prodrug may be used to alter or improvethe physical and/or pharmacokinetic profile of the parent compound andcan be formed when the parent compound contains a suitable group orsubstituent which can be derivatised to form a prodrug. Examples ofpro-drugs include in-vivo hydrolysable esters of a compound of theformula (I) or a pharmaceutically-acceptable salt thereof.

Various forms of prodrugs are known in the art, for examples see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988); and-   e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

An in-vivo hydrolysable ester of a compound of the formula (I) or apharmaceutically-acceptable salt thereof containing carboxy or hydroxygroup is, for example, a pharmaceutically-acceptable ester which ishydrolysed in the human or animal body to produce the parent acid oralcohol.

Suitable pharmaceutically-acceptable esters for carboxy include(1-6C)alkoxymethyl esters for example methoxymethyl,(1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-onylmethyl esters forexample 5-methyl-1,3-dioxolan-2-ylmethyl; and(1-6C)alkoxycarbonyloxyethyl esters for example1-methoxycarbonyloxyethyl and may be formed at any carboxy group in thecompounds of this invention.

An in-vivo hydrolysable ester of a compound of the formula (I) or apharmaceutically-acceptable salt thereof containing a hydroxy group orgroups includes inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters) and α-acyloxyalkyl ethers and relatedcompounds which as a result of the in-vivo hydrolysis of the esterbreakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkylethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Aselection of in-vivo hydrolysable ester forming groups for hydroxyinclude (1-10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyland phenylacetyl, (1-10C)alkoxycarbonyl (to give alkyl carbonateesters), di-(1-4C)alkylcarbamoyl andN-(di-(1-4C)alkylaminoethyl)-N-(1-4C)alkylcarbamoyl (to givecarbamates), di-(1-4C)alkylaminoacetyl and carboxyacetyl. Examples ofsubstituents on benzoyl and phenylacetyl include chloromethyl oraminomethyl, (1-4C)alkylaminomethyl and di-((1-4C)alkyl)aminomethyl, andmorpholino or piperazino linked from a ring nitrogen atom via amethylene linking group to the 3- or 4-position of the benzoyl ring.

Certain suitable in-vivo hydrolysable esters of a compound of theformula (I) are described within the definitions listed in thisspecification, for example esters described by the definition (Rc2d),and some groups within (Rc2c). Suitable in-vivo hydrolysable esters of acompound of the formula (I) are described as follows. For example, a1,2-diol may be cyclised to form a cyclic ester of formula (PD1) or apyrophosphate of formula (PD2):

-   -   Particularly interesting are such cyclised pro-drugs when the        1,2-diol is on a (1-4C)alkyl chain linked to a carbonyl group in        a substituent of formula Rc borne by a nitrogen atom in (TC4).        Esters of compounds of formula (I) wherein the HO-function/s in        (PD1) and (PD2) are protected by (1-4C)alkyl, phenyl or benzyl        are useful intermediates for the preparation of such pro-drugs.

Further in-vivo hydrolysable esters include phosphoramidic esters, andalso compounds of formula (I) in which any free hydroxy groupindependently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0)ester of the formula (PD3)), wherein npd is independently 0 or 1 foreach oxo group:

For the avoidance of doubt, phosphono is —P(O)(OH)₂;(1-4C)alkoxy(hydroxy)-phosphoryl is a mono-(1-4C)alkoxy derivative of—O—P(O)(OH)₂; and di-(1-4C)alkoxyphosphoryl is a di-(1-4C)alkoxyderivative of —O—P(O)(OH)₂.

Useful intermediates for the preparation of such esters includecompounds containing a group/s of formula (PD3) in which either or bothof the —OH groups in (PD3) is independently protected by (1-4C)alkyl(such compounds also being interesting compounds in their own right),phenyl or phenyl-(1-4C)alkyl (such phenyl groups being optionallysubstituted by 1 or 2 groups independently selected from (1-4C)alkyl,nitro, halo and (1-4C)alkoxy).

Thus, prodrugs containing groups such as (PD1), (PD2) and (PD3) may beprepared by reaction of a compound of formula (I) containing suitablehydroxy group/s with a suitably protected phosphorylating agent (forexample, containing a chloro or dialkylamino leaving group), followed byoxidation (if necessary) and deprotection. Prodrugs containing a groupsuch as (PS1) may be obtained by analagous chemistry.

When a compound of formula (I) contains a number of free hydroxy group,those groups not being converted into a prodrug functionality may beprotected (for example, using a t-butyl-dimethylsilyl group), and laterdeprotected. Also, enzymatic methods may be used to selectivelyphosphorylate or dephosphorylate alcohol functionalities.

Other interesting in-vivo hydrolysable esters include, for example,those in which Rc is defined by, for example, R¹⁴C(O)O(1-6C)alkyl-CO—(wherein R¹⁴ is for example, benzyloxy-(1-4C)alkyl, or phenyl). Suitablesubstituents on a phenyl group in such esters include, for example,4-(1-4C)piperazino-(1-4C)alkyl, piperazino-(1-4C)alkyl andmorpholino-(1-4C)alkyl.

Where pharmaceutically-acceptable salts of an in-vivo hydrolysable estermay be formed this is achieved by conventional techniques. Thus, forexample, compounds containing a group of formula (PD1), (PD2) and/or(PD3) may ionise (partially or fully) to form salts with an appropriatenumber of counter-ions. Thus, by way of example, if an in-vivohydrolysable ester prodrug of a compound of formula (I) contains two(PD3) groups, there are four HO—P— functionalities present in theoverall molecule, each of which may form an appropriate salt (i.e. theoverall molecule may form, for example, a mono-, di-, tri- ortetra-sodium salt).

The compounds of the present invention have a chiral centre at the C-5position of the isoxazoline ring. The pharmaceutically active enantiomeris of the formula (IA):

The present invention includes the pure enantiomer depicted above ormixtures of the 5R and 5S enantiomers, for example a racemic mixture. Ifa mixture of enantiomers is used, a larger amount (depending upon theratio of the enantiomers) will be required to achieve the same effect asthe same weight of the pharmaceutically active enantiomer. For example,the enantiomer depicted above is the 5(R) isomer when HET is 1,2,3- or1,2,4-triazole or tetrazole.

Furthermore, some compounds of the formula (I) may have other chiralcentres. It is to be understood that the invention encompasses all suchoptical and diastereo-isomers, and racemic mixtures, that possessantibacterial activity. It is well known in the art how to prepareoptically-active forms (for example by resolution of the racemic form byrecrystallisation techniques, by chiral synthesis, by enzymaticresolution, by biotransformation or by chromatographic separation) andhow to determine antibacterial activity as described hereinafter.

Furthermore, some compounds of the formula (I) may exist as cis- andtrans-isomers. It is to be understood that the invention encompasses allsuch isomers, and mixtures thereof, that possess antibacterial activity.

The invention relates to all tautomeric forms of the compounds of theformula (I) that possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I)may exhibit polymorphism, and that the invention encompasses all suchforms which possess antibacterial activity.

As stated before, we have discovered a range of compounds that have goodactivity against a broad range of Gram-positive pathogens includingorganisms known to be resistant to most commonly used antibiotics,together with activity against fastidious Gram negative pathogens suchas H.influenzae & M. catarrhalis. They have good physical and/orpharmacokinetic properties in general, and favourable toxicologicalprofiles.

Particularly preferred compounds of the invention comprise a compound offormula (I), or a pharmaceutically-acceptable salt or an in-vivohydrolysable ester thereof, wherein the substituents Q, HET, T and othersubstituents mentioned above have values disclosed hereinbefore, or anyof the following values (which may be used where appropriate with any ofthe definitions and embodiments disclosed hereinbefore or hereinafter):

In one embodiment of the invention are provided compounds of formula(I), or a pharmaceutically-acceptable salt or an in-vivo hydrolysableester thereof, in which Q, HET, T and other substituents mentioned abovehave the values disclosed hereinbefore and Rs is selected from the group(Rsb).

In one embodiment is provided a compound of formula (I) as definedherein wherein Q is selected from Q1 to Q9. In another embodiment isprovided a compound of formula (I) as defined herein wherein Q is Q10.

Preferably Q is selected from Q1, Q2, Q4, Q6 and Q9; especially Q1, Q2and Q9; more particularly Q1 and Q2; and most preferably Q is Q1.

In one embodiment T is an optionally substituted C-linked (fullyunsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3heteroatoms drawn in combination from O, N, or S, optionallysubstituted, in a position not adjacent to the linking position, by oneor more substituents independently selected from R^(4h), R^(5h) and6^(6h) defined herein.

In another embodiment T is selected from the groups of formula (TAa1) to(TAa6) defined herein.

Preferably T is selected from (TAa1 to TAa3). Especially preferred iseach of these values of T when present in Q1 and Q2, particularly in Q1.

In one embodiment Rs has values (Rsa) to (Rsc1-3).

In another embodiment Rs has values (Rsd).

Preferable Rs groups are those of (Rsa) and (Rsb).

In one aspect, suitable values of (Rsa) are halo, amino and(2-4C)cycloalkenyl.

In another aspect a suitable value of (Rsd) is cyano.

In (Rsb) the substituted (1-4C)alkyl group is preferably a substitutedmethyl group.

In one aspect, suitable values for a substituent on a (1-4C)alkyl groupin (Rsb) are cyano, azido, halo and (1-4C)alkyl-S(O)q- wherein q=0,particularly wherein the (1-4C)alkyl group is a methyl group.

In (Rsb), when the (1-4C)alkyl group is substituted by a N-linked5-membered heteroaryl ring it will be appreciated that the ring isaromatic and that when the ring is optionally substituted on anavailable carbon atom by oxo or thioxo then, when HET contains 1 to 3further nitrogen heteroatoms, one of the further nitrogen heteroatoms ispresent as NH or as N-(1-4C)alkyl. Similarly, when the ring isoptionally substituted on an available nitrogen atom by (1-4C)alkyl thenthe ring is substituted on an available carbon atom by oxo or thioxo.Preferred values for the N-linked 5-membered heteroaryl ring as asubstituent in (Rsb) are the following rings (HET-P1 to HET-P5):

In (Rsc1) to (Rsc3), particular rings are morpholino, tetrahydropyridyland dihydropyrrolyl.

Preferable (Rs) groups provided by optional F and/or Cl and/or Br and/orone cyano further substituents in (Rsa) and (Rsb) are, for example, Rsas trifluoromethyl, —CHF₂, —CH₂F, —CH₂Cl—CH₂Br, —CH₂CN,—CF₂NH(1-4C)alkyl, —CF₂CH₂OH, —CH₂OCF₃, —CH₂OCHF₂, —CH₂OCH₂F, —NHCF₂CH₃.

In another embodiment, T is selected from TAa1 and TAa2. In a furtherembodiment, T is TAa1.

Preferably R^(6h) is hydrogen or (1-4C)alkyl, and R^(4h) and R^(5h) areindependently selected from hydrogen, cyano, (1-4C)alkoxycarbonyl,—CONRvRw, hydroxy(1-4C)alkyl, NRvRw(1-4C)alkyl, —NRcRv(1-4C)alkyl;wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl};Rc is as hereinbefore defined.

More preferably, R^(5h) and R^(6h) are hydrogen and R^(4h) is selectedfrom cyano, (1-4C)alkoxycarbonyl, —CONRcRv (preferably with Rc ashydrogen or (1-4C)alkyl), hydroxy-(1-4C)alkyl and —NRcRv(1-4C)alkyl;wherein Rv is hydrogen or (1-4C)alkyl and Rc is preferably (Rc2) ashereinbefore defined (especially wherein R¹³ is (Rc2c) as hereinbeforedefined).

When R^(4h) and R^(5h) are independently selected from optionallysubstituted (as defined) (1-4C)alkyl, preferably there are one or twosubstituents, most especially just one substituent; and when theoptional substituent is —CONRcRv or —NRcRv, Rc is preferably hydrogen,(1-4C)alkyl or (1-4C)alkanoyl.

The above preferred values of (TAa) are particularly preferred whenpresent in Q1 or Q2, especially Q1. Most preferable is (TAa1) withpreferable R^(4h) substituents as hereinbefore defined.

Preferable values for other substituents (which may be used whereappropriate with any of the definitions and embodiments disclosedhereinbefore or hereinafter) are:

-   (a) In one embodiment HET is a 6-membered heteroaryl as defined    herein, and in another embodiment HET is a 5-membered heteroaryl as    defined herein.-   (b) When HET is a 5-membered heteroaryl as defined herein,    preferably HET is 1,2,3-triazole (especially 1,2,3-triazol-1-yl),    1,2,4-triazole (especially 1,2,4-triazol-1-yl) and tetrazole    (preferably tetrazol-2-yl).-   (c) When HET is a 6-membered heteroaryl as defined herein,    preferably HET is a di-hydro version of pyrimidine, pyridazine,    pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine and    pyridine.-   (d) In one aspect, preferably HET is unsubstituted. In another    aspect HET is substituted as described in any embodiment or aspect    described herein.-   (e) In one aspect preferably one of R² and R³ is hydrogen and the    other fluoro. In another aspect both R² and R³ are fluoro.-   (f) Preferably Rc is R¹³CO— and preferably R¹³ is    (1-4C)alkoxycarbonyl, hydroxy(1-4C)alkyl, (1-4C)alkyl (optionally    substituted by one or two hydroxy groups, or by an (1-4C)alkanoyl    group), (1-4C)alkylamino, dimethylamino(1-4C)alkyl,    (1-4C)alkoxymethyl, (1-4C)alkanoylmethyl,    (1-4C)alkanoyloxy(1-4C)alkyl, (1-5C)alkoxy or 2-cyanoethyl.-   (g) More preferably R¹³ is 1,2-dihydroxyethyl,    1,3-dihydroxyprop-2-yl, 1,2,3-trihydroxyprop-1-yl, methoxycarbonyl,    hydroxymethyl, methyl, methylamino, dimethylaminomethyl,    methoxymethyl, acetoxymethyl, methoxy, methylthio, naphthyl,    tert-butoxy or 2-cyanoethyl.-   (h) Particularly preferred as R¹³ is 1,2-dihydroxyethyl,    1,3-dihydroxyprop-2-yl or 1,2,3-trihydroxyprop-1-yl.-   (i) In another aspect preferably R¹³ is hydrogen, (1-10C)alkyl    [optionally substituted by one or more hydroxy] or    R¹⁴C(O)O(1-6C)alkyl.

For compounds of formula (I) preferred values for Rc are those in group(Rc2) when present in any of the definitions herein containing Rc.

In the definition of (Rc2c) the AR2a, AR2b, AR3a and AR3b versions ofAR2 and AR3 containing groups are preferably excluded.

Especially preferred compounds of the present invention are of theformula (IB):

-   wherein HET is 1,2,3-triazole (especially 1,2,3-triazol-1-yl),    1,2,4-triazole (especially 1,2,4-triazol-1-yl) and tetrazole    (preferably tetrazol-2-yl) or HET is a di-hydro version of    pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine,    1,3,5-triazine and pyridine;-   R² and R³ are independently hydrogen or fluoro; and-   T is selected from (TAa1 to TAa6), or in-vivo hydrolysable esters or    pharmaceutically-acceptable salts thereof.

Further especially preferred compounds of the invention are of theformula (IB) wherein HET is 1,2,3-triazole (especially1,2,3-triazol-1-yl), 1,2,4-triazole (especially 1,2,4-triazol-1-yl) ortetrazole (preferably tetrazol-2-yl;

-   R² and R³ are independently hydrogen or fluoro;-   T is selected from (TAa1 & 2), or in-vivo hydrolysable esters or    pharmaceutically-acceptable salts thereof.

In the above aspects and preferred compounds of formula (IB), in (TAa1to TAa6), preferably R^(5h) and R^(6h) are hydrogen and R^(4h) isselected from cyano, (1-4C)alkoxycarbonyl, —CONRcRv (preferably with Rcas hydrogen or (1-4C)alkyl), hydroxy-(1-4C)alkyl and —NRcRv(1-4C)alkyl;wherein Rv is hydrogen or (1-4C)alkyl and Rc is as defined in (Rc2) andespecially R¹³CO— wherein R¹³ is preferably (1-4C)alkoxycarbonyl,hydroxy(1-4C)alkyl, (1-4C)alkyl (optionally substituted by one or twohydroxy groups, or by an (1-4C)alkanoyl group), (1-4C)alkylamino,dimethylamino(1-4C)alkyl, (1-4C)alkoxymethyl, (1-4C)alkanoylmethyl,(1-4C)alkanoyloxy(1-4C)alkyl, (1-5C)alkoxy or 2-cyanoethyl).

In the above aspects and preferred compounds of formula (IB), preferableoptional substituents Rs on HET are fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, bromomethyl, cyanomethyl, cyano, amino,azido, alkylthioalkyl such as methylthiomethyl, or 2-propynyl.

In all of the above aspects and preferred compounds of formula (IB),in-vivo hydrolysable esters are preferred where appropriate, especiallyphosphoryl esters (as defined by formula (PD3) with npd as 1).

In all of the above definitions the preferred compounds are as shown informula (IA). Particular compounds of the present invention include thefollowing Examples, in particular Examples No. 1, and No. 3 and theindividual (5R) isomers thereof.

Process Section:

In a further aspect the present invention provides a process forpreparing a compound of formula (I) or a pharmaceutically-acceptablesalt or an in-vivo hydrolysable ester thereof. It will be appreciatedthat during certain of the following processes certain substituents mayrequire protection to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject, for example, ‘Protective Groups in Organic Synthesis’ byTheodora Green (publisher: John Wiley & Sons).

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulfuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Resins may also be used as a protecting group.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

A compound of the formula (I), or a pharmaceutically-acceptable salt oran in-vivo hydrolysable ester thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Such processes, when used to prepare a compound of theformula (I), or a pharmaceutically-acceptable salt or an in-vivohydrolysable ester thereof, are provided as a further feature of theinvention and are illustrated by the following representative examples.Necessary starting materials may be obtained by standard procedures oforganic chemistry (see, for example, Advanced Organic Chemistry(Wiley-Interscience), Jerry March). The preparation of such startingmaterials is described within the accompanying non-limiting Examples (inwhich, for example, 3,5-difluorophenyl, 3-fluorophenyl and(des-fluoro)phenyl containing intermediates may all be prepared byanalagous procedures; or by alternative procedures—for example, thepreparation of (T group)-(fluoro)phenyl intermediates by reaction of a(fluoro)phenylstannane with, for example, a pyran or(tetrahydro)pyridine compound, may also be prepared by anion chemistry(see, for example, WO97/30995).

Alternatively, necessary starting materials are obtainable by analogousprocedures to those illustrated which are within the ordinary skill ofan organic chemist. Information on the preparation of necessary startingmaterials or related compounds (which may be adapted to form necessarystarting materials) may also be found in the following Patent andApplication Publications, the contents of the relevant process sectionsof which are hereby incorporated herein by reference: WO99/02525;WO98/54161; WO97/37980; WO97/30981 (& U.S. Pat. No. 5,736,545);WO97/21708 (& U.S. Pat. No. 5,719,154); WO97/10223; WO97/09328;WO96/35691; WO96/23788; WO96/15130; WO96/13502; WO95/25106 (& U.S. Pat.No. 5,668,286); WO95/14684 (& U.S. Pat. No. 5,652,238); WO95/07271 (&U.S. Pat. No. 5,688,792); WO94/13649; WO94/01110; WO93/23384 (& U.S.Pat. No. 5,547,950 & U.S. Pat. No. 5,700,799); WO93/09103 (& U.S. Pat.No. 5,565,571, U.S. Pat. No. 5,654,428, U.S. Pat. No. 5,654,435, U.S.Pat. No. 5,756,732 & U.S. Pat. No. 5,801,246); U.S. Pat. No. 5,231,188;U.S. Pat. No. 5,247,090; U.S. Pat. No. 5,523,403; WO97/27188;WO97/30995; WO97/31917; WO98/01447; WO98/01446; WO99/10342; WO99/10343;WO99/11642; WO99/64416; WO99/64417 and GB99/03299; European PatentApplication Nos. 0,359,418 and 0,609,905; 0,693,491 A1 (& U.S. Pat. No.5,698,574); 0,694,543 A1 (& AU 24985/95); 0,694,544 A1 (& CA 2,154,024);0,697,412 A1 (& U.S. Pat. No. 5,529,998); 0,738,726 A1 (& AU 50735/96);0,785,201 A1 (& AU 10123/97); German Patent Application Nos. DE 195 14313 A1 (& U.S. Pat. No. 5,529,998); DE 196 01 264 A1 (& AU 10098/97); DE196 01 265 A1 (& AU 10097/97); DE 196 04 223 A1 (& AU 12516/97); DE 19649 095 A1 (& AU 12517/97).

The following Patent and Application Publications may also provideuseful information and the contents of the relevant process sections arehereby incorporated herein by reference: FR 2458547; FR 2500450(& GB2094299, GB 2141716 & U.S. Pat. No. 4,476,136); DE 2923295 (& GB2028306, GB 2054575, U.S. Pat. No. 4,287,351, U.S. Pat. No. 4,348,393,U.S. Pat. No. 4,413,001, U.S. Pat. No. 4,435,415 & U.S. Pat. No.4,526,786), DE 3017499 (& GB 2053196, U.S. Pat. No. 4,346,102 & U.S.Pat. No. 4,372,967); U.S. Pat. No. 4,705,799; European PatentApplication Nos. 0,312,000; 0,127,902; 0,184,170; 0,352,781; 0,316,594.

The skilled organic chemist will be able to use and adapt theinformation contained and referenced within the above references toobtain necessary starting materials.

Thus, the present invention also provides that the compounds of theformulae (I) and pharmaceutically-acceptable salts and in-vivohydrolysable esters thereof, can be prepared by a process (a) to (i) asfollows (wherein the variables are as defined hereinbefore or afterunless otherwise stated)

-   (a) by modifying a substituent in or introducing a substituent into    another compound of formula (I); such changes may be usefully made    in many positions of compounds of formula (I), for instance a    heterocyclyl group linked through nitrogen (optionally substituted    on a carbon other than a carbon atom adjacent to the linking    nitrogen ring atom) may be converted into another heterocyclyl group    linked through nitrogen (optionally substituted on a carbon other    than a carbon atom adjacent to the linking nitrogen ring atom) by    introduction of a new ring substituent or by refunctionalisation of    an existing ring substituent, for instance by modifying the    4-substituent of a 4-substituted 1,2,3-triazol-1-yl group; or for    instance such changes may be usefully made in the group Q; for    example an alkylthio group may be oxidised to an alkylsulfinyl or    alkysulfonyl group, for instance a group R^(4h) that contains an    alkylthio group may be oxidized to an alkylsulfinyl or alkylsulfonyl    group or for example a group R^(4h) that contains an amino group may    be converted into its acylamino derivative in the last step of the    preparation of a compound of the formula (I);    or-   (b) by reaction of a compound of formula (II):-    wherein Y is a displaceable group (which may be (i) generated    in-situ, for example under Mitsunobu conditions, or (ii) preformed,    such as chloro or mesylate) with a compound of the formula (III):    HET  (III)-    wherein HET is HET-H free-base form or HET-anion formed from the    free base form; or-   (c) by reaction of a compound of the formula (IV):    Q-Z  (IV)-    wherein Z is an isocyanate, amine or urethane group with an epoxide    of the formula (V):    or-   (d) by reaction of a compound of formula (VI):-    wherein Y′ is a group HET as hereinabove defined, X is a    replaceable substituent—such as chloride, bromide, iodide,    trifluoromethylsulfonyloxy, trimethylstannyl, trialkoxysilyl, or a    boronic acid residue—located at a position substituted by T in any    of the aromatic embodiments Q1-Q8 of Qn as hereinabove defined for    Q, but with X in place of the substituent T, with a compound of the    formula (VII):    T-X′  (VII)-    wherein T-X′ is a five-membered heterocycle with 1-3 heteroatoms    drawn in combination from O, N, and S and X′ is a replaceable    C-linked substituent—such as chloride, bromide, iodide,    trifluoromethylsulfonyloxy, trimethylstannyl, trialkoxysilyl, or a    boronic acid residue; wherein the substituents X and X′ are chosen    to be complementary pairs of substituents known in the art to be    suitable as complementary substrates for coupling reactions    catalysed by transition metals such as palladium(0); or-   (e) by reaction of a compound of formula (VIII):-    wherein Y′ is a group HET as defined herein above and X1 and X2    here are independently optionally substituted heteroatoms drawn in    combination from O, N, and S such that C(X1)X2 constitutes a    substituent that is a carboxylic acid derivative substituent located    at a position substituted by T in any of the aromatic embodiments    Q1-Q10 of Qn as hereinabove defined for Q with a compound of the    formula (IX) and X3 and X4 are independently optionally substituted    heteroatoms drawn in combination from O, N, and S:-    and wherein one of C(X1)X2 and C(X3)X4 constitutes an optionally    substituted hydrazide, thiohydrazide, or amidrazone, and the other    one of C(X1))X2 and C(X3)X4 constitutes an optionally substituted    acylating, thioacylating, or imidoylating agent such that C(X1)X2    and C(X3)X4 may be condensed together to form a 5-membered    heterocycle containing 3 heteroatoms drawn in combination from O, N,    and S, for instance thiadiazole, by methods well-known in the art;    or-   (f) by reaction of a compound of formula (X):-    wherein Y′ is a group HET as defined herein above and C(X5)X6    constitutes a substituent located at a position substituted by T in    any of the aromatic embodiments Q1-Q8 of Qn as hereinabove defined    for Q with a compound of the formula (XI):-    wherein one of C(X5)X6 and C(X7)X8 constitutes an optionally    substituted alpha-(leaving-group-substituted)ketone, wherein the    leaving group is for example a halo-group or an (alkyl or    aryl)-sulfonyloxy-group, and the other one of C(X5)X6 and C(X7)X8    constitutes an optionally substituted amide, thioamide, or amidine,    such that C(X5)X6 and C(X7)X8 are groups that may be condensed    together to form a 5-membered heterocycle containing 2 heteroatoms    drawn in combination from O, N, and S, for instance thiazole, by    methods well-known in the art; or-   (g) for HET as optionally substituted 1,2,3-triazoles, compounds of    the formula (I) may be made by cycloaddition via the azide (wherein    e.g. Y in (II) is azide) to acetylenes, or to acetylene equivalents    such as optionally substituted cylcohexa-1,4-dienes or optionally    substituted ethylenes bearing eliminatable substituents such as    arylsulfonyl; or-   (h) for HET as 4-substituted 1,2,3-triazole compounds of formula (I)    may be made by reacting aminomethylisoxazolines with    1,1-dihaloketone sulfonylhydrazones;-   (i) for HET as 4-substituted 1,2,3-triazole compounds of formula (I)    may also be made by reacting azidomethyl isoxazolines with terminal    alkynes using Cu(1) catalysis;    and thereafter if necessary: (i) removing any protecting    groups; (ii) forming a pharmaceutically-acceptable salt; (iii)    forming an in-vivo hydrolysable ester.-   (a) Methods for converting substituents into other substituents are    known in the art by using standard chemistry (see for example,    Comprehensive Organic Functional Group Transformations (Pergamon),    Katritzky, Meth-Cohn & Rees); for example: a hydroxy group may be    converted into a silyloxy group; an azido or an acylamino or    thioacylamino group, for instance an acetamide group (optionally    substituted or protected on the amido-nitrogen atom); into an    acyloxy group, for instance an acetoxy group; a heterocyclylamino    group (optionally substituted or protected on the amino-nitrogen    atom), for instance an isoxazol-3-ylamino group or a    1,2,5-thiadiazol-3-ylamino group; a heterocyclyl group linked    through nitrogen (optionally substituted on a carbon other than a    carbon atom adjacent to the linking nitrogen ring atom), for    instance an optionally substituted 1,2,3-triazol-1-yl group; or an    amidino group, for instance an 1-(N-cyanoimino)ethylamino group; a    hydroxy group may be alkylated to a methoxy group, a hydroxy group    may be converted into a halo-group, or into a cyano- group; or into    an alkylthio-, an arylthio- or a heteroarylthio-group (see, for    example, Tet. Lett., 585, 1972); such conversions of the hydroxy    group taking place directly (for instance by acylation or Mitsunobu    reaction) or through the intermediacy of one or more derivatives    (for instance a mesylate or an azide); moreover, a hydroxy-group may    be oxidized to a carbonyl group including a carboxylic acid group.    an acyloxy group may be converted into a hydroxy group or into the    groups that may be obtained from a hydroxy group (either directly or    through the intermediacy of a hydroxy group);-   a silyloxy group may be converted into a hydroxy group or into the    groups that may be obtained from a hydroxy group (either directly or    through the intermediacy of a hydroxy group);-   an acylamino group or thioacylamino group may be converted into    another acylamino group or thioacylamino group; or into a    heterocyclylamino group (optionally substituted or protected on the    amino-nitrogen atom);-   a carboxylic acid group may be converted into an ester or an amide,    an ester may be converted into a carboxylic acid or an amide, and an    amide may be converted into an acid or a nitrile; a nitrile may be    converted into a carboxylic acid or an amide or an imidate.-   an imidate or a nitrile may be converted into a wide range of 5    membered heterocycles such as tetrazoles or 1,2,4-triazoles;-   a carbonyl group can be reduced to a hydroxy group and a carboxylic    acid group or a derivative thereof can be reduced to a carbonyl    group or to a hydroxy group; a carbonyl group may also be converted    into a CF₂ group and a carboxylic acid group may be converted into a    CF₃ group;-   an alkylthio group may be oxidised to an alkylsulfinyl or    alkysulfonyl group;-   a cyano group may be reduced to an amino group, a nitro group may be    reduced to an amino group; a carbonyl group may be converted into a    thiocarbonyl group (eg. using Lawsson's reagent) or a bromo group    converted to an alkylthio group. It is possible in this way and in    closely analogous ways using standard methods well known to skilled    organic chemists to interconvert compounds of formula (I).-   (b)(i) Reaction (b)(i) (in which Y is initially hydroxy) is    performed under Mitsunobu conditions, for example, in the presence    of tri-n-butylphosphine and diethyl azodicarboxylate (DEAD) in an    organic solvent such as THF, and in the temperature range 0° C.-60°    C., but preferably at ambient temperature. Details of Mitsunobu    reactions are contained in Tet. Letts., 31, 699, (1990); The    Mitsunobu Reaction, D. L. Hughes, Organic Reactions, 1992, Vol. 42,    335-656 and Progress in the Mitsunobu Reaction, D. L. Hughes,    Organic Preparations and Procedures International, 1996, Vol. 28,    127-164.-   (b)(ii) Reactions (b)(ii) are performed conveniently in the presence    of a suitable base such as, for example, an alkali or alkaline earth    metal carbonate, alkoxide or hydroxide, for example sodium carbonate    or potassium carbonate, or, for example, an organic amine base such    as, for example, pyridine, 2,6-lutidine, collidine,    4-dimethylaminopyridine, triethylamine, morpholine or    diazabicyclo-[5.4.0]undec-7-ene, the reaction is also preferably    carried out in a suitable inert solvent or diluent, for example    methylene chloride, acetonitrile, tetrahydrofuran,    1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide,    N-methylpyrrolidin-2-one or dimethylsulfoxide at and at a    temperature in the range 25-60° C.

When Y is chloro, the compound of the formula (II) may be formed byreacting a compound of the formula (II) wherein Y is hydroxy (hydroxycompound) with a chlorinating agent. For example, by reacting thehydroxy compound with thionyl chloride, in a temperature range ofambient temperature to reflux, optionally in a chlorinated solvent suchas dichloromethane or by reacting the hydroxy compound with carbontetrachloride/triphenyl phosphine in dichloromethane, in a temperaturerange of 0° C. to ambient temperature. A compound of the formula (II)wherein Y is chloro or iodo may also be prepared from a compound of theformula (II) wherein Y is mesylate or tosylate, by reacting the lattercompound with lithium chloride or lithium iodide and crown ether, in asuitable organic solvent such as THF, in a temperature range of ambienttemperature to reflux

When Y is (1-4C)alkanesulfonyloxy or tosylate the compound (II) may beprepared by reacting the hydroxy compound with (1-4C)alkanesulfonylchloride or tosyl chloride in the presence of a mild base such astriethylamine or pyridine.

When Y is a phosphoryl ester (such as PhO₂—P(O)—O—) or Ph₂-P(O)—O— thecompound (II) may be prepared from the hydroxy compound under standardconditions.

If not commercially available, compounds of the formula (III) may beprepared by procedures which are selected from standard chemicaltechniques, techniques which are analogous to the synthesis of known,structurally similar compounds, or techniques which are analogous to theprocedures described in the Examples. For example, standard chemicaltechniques are as described in Houben Weyl.

-   (c) by reaction of Q-Z wherein Z is an amine, urethane, or    isocyanate with an N-epoxypropyl hetercycle (V). Epoxides of the    formula (V) may be prepared from the corresponding    N-allylheterocycle of formula (XII):

Certain such epoxide and alkene intermediates are novel and are providedas a further feature of the invention. Asymmetric epoxidation may beused to give the desired optical isomer. Furthermore, a similar reactionto reaction (c) may be performed in which Q-Z (wherein Z is a aminegroup) is reacted with the epoxide (V) (optionally in the presence of anorganic base), and the product is reacted with, for example, phosgene toform the oxazolidinone ring.

Alternatively, a precursor of the group HET may be incorporated in placeof the group HET in the epoxide of formula (V).

Variations on this process in which the oxirane is replaced by anequivalent reagent X—CH₂CH(O-optionally protected)CH₂HET where X is adisplaceable group are also well known in the art.

Such reactions and the preparation of starting materials in within theskill of the ordinary chemist with reference to the above-citeddocuments disclosing analogous reactions and preparations.

In particular, compounds of the formula (II), and (IV) may be preparedby the skilled man, for example as described in International PatentApplication Publication Nos. cited herein, and by analogous processes.

Compounds of the formula (II) wherein Y is hydroxy may be obtained asdescribed in the references cited herein, for example, by reacting acompound Q-Z (IV) where Z is an amine, an isocyanate, or a urethane,especially a compound of the formula (IV, Z=NHCO₂R²¹) with a compound offormula (XIII):

wherein R²¹ is (1-6C)alkyl or benzyl and R²² is (1-4C)alkyl or—S(O)_(n)(1-4C)alkyl where n is 0, 1 or 2. Preferably R²² is(1-4C)alkyl. Compounds of the formula (II), (IV), and (XIII) may beprepared by the skilled man, for example as described in InternationalPatent Application Publication Nos. cited herein, the contents of whichare hereby incorporated by reference, and by analogous processes.

Compounds of the formula Q-Z wherein Z is a urethane may be prepared bythe skilled chemist, for example by analogous processes to thosedescribed in International Patent Application Publication Nos. WO97/30995 and WO 97/37980. Compounds of the formula Q-Z wherein Z is anisocyanate may be prepared by the skilled chemist, for example byanalogous processes to those described in Walter A. Gregory et al in J.Med. Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J. Med. Chem.1992, 35, 1156-1165.

-   (d) Compounds of formula (II) wherein Y is is HET as hereinabove    defined or Y is a group that may be converted to HET, such as    hydroxy, may be obtained by coupling together two appropriately    substituted fragments to form a carbon-carbon bond in the place of    the two substituents X and X′ of (VI) and (VII) respectively. X and    X′ may be selected from substituents such as chloro, bromo, iodo,    trifluoromethanesulfonyloxy, trialkylstannyl, trialkoxysilyl, or a    boronic acid residue provided that the selected substituents X and    X′ form a pair of complementary substituents known in the art to be    suitable pairs of substituents for transition metal mediated    reactions. For instance one of X and X′ prime may be chloro and the    other may be trimethylstannyl, as shown in the Scheme.

If not commercially available, the X and X′ substituted fragments usedas coupling partners in the transition metal mediated coupling reactionmay be prepared by procedures that are selected from standard chemicaltechniques, techniques that are analogous to the synthesis of known,structurally similar compounds, or techniques which are analogous to theprocedures described in the Examples. For example, standard chemicaltechniques are described in Houben Weyl, Methoden der OrganischenChemie.

-   -   The chemistry of process (e) may also be utilised to prepare        compounds of formula (II) wherein Y is hydroxy or a group that        may be converted into a HET ring, and then process (b) or other        suitable chemistry used to prepare compounds of formula (I).

-   (e) The reaction between thioacylhydrazides and acylating agents to    form intermediate acylthioacylhydrazides and subsequently    1,3,4-thiadiazoles is performed under conventional conditions, for    instance as indicated in Comprehensive Heterocyclic Chemistry.    Suitable acylating agents include acid chlorides and anhydrides.    Either of the reaction components may constitute the    thioacylhydrazide and the other constitutes the acylating agent,    according to synthetic convenience.

The intermediate acylthioacylhydrazides may also be converted into1,3,4-oxadiazoles. Carboxylic acid derivatives other thanthioacylhydrazide are also well known in the art to be substrates forsimilar reactions leading to other C-linked 5-membered heterocyclescontaining 3 heteroatoms. For instance, acylhydrazides and amidrazonesmay be used in place of thioacylhydrazides and thioacylataing agentssuch as methyl dithioacetate and imidolyating agents such as ethylacetimidate may be used in place of acylating agents. The products ofsuch reactions are well known in the art. Thus, acylation ofacylhydrazides and cyclisation of the resultant diacylhydrazides isknown to give 1,3,4-oxadiazoles and acylation amidrazones andcyclisation of the resultant acylamidrazones is known to give1,2,4-triazoles. Such reactions are described in the literature asindicated in e.g. Comprehensive Heterocyclic Chemistry and areincorporated by reference into the process of method (e). It is furtherwell known that these reactions, for instance the reaction between a(thio)acylating agent and a (thio)hydrazide proceed stepwise to give acyclic product and that the reactions proceed through intermediates thatcan themselves be isolated under appropriate reaction conditions.Accordingly this method also includes a process in which an isolableintermediate for instance as di(thio)acylhydrazide is converted into acompound of formula (I) under the conditions already well known forreactions of this type. Moreover, an intermediate in this reaction maybe produced under conditions where the cyclization to a compound offormula (I) proceeds spontaneously and without isolation of theintermediate compound, for instance in the conversion of adiacylhydrazide into a thiadiazole under conditions where monothio ordithio diacylhydrazides are formed from the diacylhydrazide and forexample Lawesson's reagent. Accordingly this method also includes aprocess in which an intermediate of the process (e) is formed andspontaneously consumed to give a compound of formula (I) under theconditions already well known for reactions of process (e).

If not commercially available, compounds of the formula (VIII) and (IX)may be prepared by procedures which are selected from standard chemicaltechniques, techniques which are analogous to the synthesis of known,structurally similar compounds, or techniques which are analogous to theprocedures described in the Examples. For example, standard chemicaltechniques are as described in Houben Weyl.

Certain such thioacylhydrazide and acylating intermediates are novel andare provided as a further feature of the invention (R, Y and Y′ suitableto give compounds of formula (I)).

-   (f) The reaction between thioamides and alpha-haloketones to form    thiazoles is performed under conventional conditions, for instance    as indicated in Comprehensive Heterocyclic Chemistry, The Chemistry    of the Thioamide Group, or Thiazoles (Heterocyclic Chemistry,    Weisberger). Suitable halogens include bromine and chlorine. It is    well known that other leaving groups may be suitable alternatives to    the halogen of an alpha-haloketone, for instance methansulfonyloxy-    or hydroxy-ketones or diazoketones may also be used in reaction (f).    The regioisomer of thiazole obtained by this method depends on which    reaction partner constitutes the thioamide and which reaction    partner constitutes the alpha-(leaving-group)substituted-ketone. In    the reaction shown in the Scheme the thiazole produced is C2-linked.    Carboxylic acid derivatives other than thioamide are also well known    in the art to be substates for similar reactions leading to other    C-linked 5-membered heterocycles. Such analogous reactions are    described in e.g. Comprehensive Heterocyclic Chemistry and are    incorporated by reference into the process of method (f). It is    further well known that the reaction between an    alpha-(leaving-group)substituted-ketone and a thioamide proceeds    stepwise to give a 4-hydroxy-4,5-dihydrothiazole as one of the    intermediates and that this intermediate can be isolated under    appropriate reaction conditions. Accordingly this method also    includes a process in which an isolated    4-hydroxy-4,5-dihydrothiazole is converted into a compound of    formula (I) under dehydrating conditions already well known for    reactions of this type.

If not commercially available, compounds of the formula (X) and (XI) maybe prepared by procedures which are selected from standard chemicaltechniques, techniques which are analogous to the synthesis of known,structurally similar compounds, or techniques which are analogous to theprocedures described in the Examples. For example, standard chemicaltechniques are as described in Houben Weyl. Certain such thioamide andhaloketone intermediates are novel and are provided as a further featureof the invention.

-   (g) The cycloaddition reaction to form 1,2,3 triazoles from the    corresponding azide is performed under conventional conditions. The    reaction may use acetylenes or equivalent synthons that react as    olefins and then eliminate the elements of a molecule to regenerate    a double bond between the carbon atoms of the original olefin.    Suitable olefins or their close analogues, which include those able    to eliminate the elements of cyclopentadiene, of optionally    substituted naphthalenes, of secondary amines, or of sulfinic or    sulfenic acids, have been described in the litereature as    equivalents to or as synthons for alkynes. The method is illustrated    in the Schemes.-   (g) 4-Substituted 1,2,3-triazoles may be constructed from a primary    amino compound according to the method of Sakai et al. by reacting    it with sulfonylhydrazones of 1,1-dihalomethylketones. (see for    example Sakai et al., Bull. Chem. Soc. Japan, 1985, 59, 179); as    illustrated in the Schemes;-   (i) 4-Substituted 1,2,3-triazoles may be constructed from terminal    alkynes in a mild and regioselective reaction according to the    method of Sharpless.(see V. V. Rostov, L. G. Green, V. V. Folkin,    and K. B. Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596); ); as    illustrated in the Schemes; The preparation of suitable alkynes or    their close analogues from simpler commercially available acetylenes    such as acetylene itself or trimethylsilylacetylene is well-known in    the chemical literature;

Compounds of the formula (II) wherein Y is azide may be obtained asdescribed in the references cited herein (particularly in the sectionproceeding the discussion of protecting groups), for example from thecorresponding compounds in which Y is hydroxy or mesylate.

The main synthetic routes are illustrated in the Schemes below (with Qas phenyl, and X, R and A defined with reference to analogoussubstituents defined elsewhere herein). The compounds of the inventionmay be prepared by analogous chemistry adapted from the Schemes. TheSchemes also show the preparation of 1,2,3-triazoles via the azide(prepared from the relevant hydroxy compound).

The Schemes may be genericised by the skilled man to apply to compoundswithin the present specification which are not specifically illustratedin the Schemes (for example to HET as a 6-membered ring as definedherein).

Deprotection, salt formation or in-vivo hydrolysable ester formation mayeach be provided as a specific final process step.

The N-linked hetereocycle can of course be prepared early in the overallsynthesis, and then other functional groups changed.

Where Y is a displaceable group, suitable values for Y are for example,a halogeno or sulfonyloxy group, for example a chloro, bromo,methanesulfonyloxy or toluene-4-sulfonyloxy group.

General guidance on reaction conditions and reagents may be obtained inAdvanced Organic Chemistry, 4th Edition, Jerry March (publisher: J.Wiley & Sons), 1992. Necessary starting materials may be obtained bystandard procedures of organic chemistry, such as described in thisprocess section, in the Examples section or by analogous procedureswithin the ordinary skill of an organic chemist. Certain references arealso provided which describe the preparation of certain suitablestarting materials, for example International Patent ApplicationPublication No. WO 97/37980, the contents of which are incorporated hereby reference. Processes analogous to those described in the referencesmay also be used by the ordinary organic chemist to obtain necessarystarting materials.

The removal of any protecting groups, the formation of apharmaceutically-acceptable salt and/or the formation of an in-vivohydrolysable ester are within the skill of an ordinary organic chemistusing standard techniques. Furthermore, details on the these steps, forexample the preparation of in-vivo hydrolysable ester prodrugs has beenprovided in the section above on such esters, and in certain of thefollowing non-limiting Examples.

When an optically active form of a compound of the formula (I) isrequired, it may be obtained by carrying out one of the above proceduresusing an optically active starting material (formed, for example, byasymmetric induction of a suitable reaction step), or by resolution of aracemic form of the compound or intermediate using a standard procedure,or by chromatographic separation of diastereoisomers (when produced).Enzymatic techniques may also be useful for the preparation of opticallyactive compounds and/or intermediates.

Similarly, when a pure regioisomer of a compound of the formula (I) isrequired, it may be obtained by carrying out one of the above proceduresusing a pure regioisomer as a starting material, or by resolution of amixture of the regioisomers or intermediates using a standard procedure.

According to a further feature of the invention there is provided acompound of the formula (I), or a pharmaceutically-acceptable salt, orin-vivo hydrolysable ester thereof for use in a method of treatment ofthe human or animal body by therapy.

According to a further feature of the present invention there isprovided a method for producing an antibacterial effect in a warmblooded animal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a compound of thepresent invention, or a pharmaceutically-acceptable salt, or in-vivohydrolysable ester thereof.

The invention also provides a compound of the formula (I), or apharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof,for use as a medicament; and the use of a compound of the formula (I) ofthe present invention, or a pharmaceutically-acceptable salt, or in-vivohydrolysable ester thereof, in the manufacture of a medicament for usein the production of an antibacterial effect in a warm blooded animal,such as man.

In order to use a compound of the formula (I), an in-vivo hydrolysableester or a pharmaceutically-acceptable salt thereof, including apharmaceutically-acceptable salt of an in-vivo hydrolysable ester,(hereinafter in this section relating to pharmaceutical composition “acompound of this invention”) for the therapeutic (includingprophylactic) treatment of mammals including humans, in particular intreating infection, it is normally formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula(I), an in-vivo hydrolysable ester or a pharmaceutically-acceptable saltthereof, including a pharmaceutically-acceptable salt of an in-vivohydrolysable ester, and a pharmaceutically-acceptable diluent orcarrier.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by oral, rectal or parenteral administration. For thesepurposes the compounds of this invention may be formulated by meansknown in the art into the form of, for example, tablets, capsules,aqueous or oily solutions or suspensions, (lipid) emulsions, dispersiblepowders, suppositories, ointments, creams, aerosols (or sprays), dropsand sterile injectable aqueous or oily solutions or suspensions.

In addition to the compounds of the present invention the pharmaceuticalcomposition of this invention may also contain or be co-administered(simultaneously, sequentially or separately) with one or more knowndrugs selected from other clinically useful antibacterial agents (forexample, β-lactams or aminoglycosides) and/or other anti-infectiveagents (for example, an antifungal triazole or amphotericin). These mayinclude carbapenems, for example meropenem or imipenem, to broaden thetherapeutic effectiveness. Compounds of this invention may also containor be co-administered with bactericidal/permeability-increasing protein(BPI) products or efflux pump inhibitors to improve activity againstgram negative bacteria and bacteria resistant to antimicrobial agents.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 1 mg and 1 g of a compound of thisinvention, preferably between 100 mg and 1 g of a compound. Especiallypreferred is a tablet or capsule which contains between 50 mg and 800 mgof a compound of this invention, particularly in the range 100 mg to 500mg.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection, forexample an injection which contains between 0.1% w/v and 50% w/v(between 1 mg/ml and 500 mg/ml) of a compound of this invention.

Each patient may receive, for example, a daily intravenous, subcutaneousor intramuscular dose of 0.5 mgkg−¹ to 20 mgkg−¹ of a compound of thisinvention, the composition being administered 1 to 4 times per day. Inanother embodiment a daily dose of 5 mgkg−¹ to 20 mgkg−¹ of a compoundof this invention is administered. The intravenous, subcutaneous andintramuscular dose may be given by means of a bolus injection.Alternatively the intravenous dose may be given by continuous infusionover a period of time. Alternatively each patient may receive a dailyoral dose which may be approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day.

A pharmaceutical composition to be dosed intravenously may containadvantageously (for example to enhance stability) a suitablebactericide, antioxidant or reducing agent, or a suitable sequesteringagent.

In the above other, pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

Antibacterial Activity:

The pharmaceutically-acceptable compounds of the present invention areuseful antibacterial agents having a good spectrum of activity in-vitroagainst standard Gram-positive organisms, which are used to screen foractivity against pathogenic bacteria. Notably, thepharmaceutically-acceptable compounds of the present invention showactivity against enterococci, pneumococci and methicillin resistantstrains of S.aureus and coagulase negative staphylococci, together withhaemophilus and moraxella strains. The antibacterial spectrum andpotency of a particular compound may be determined in a standard testsystem.

The (antibacterial) properties of the compounds of the invention mayalso be demonstrated and assessed in-vivo in conventional tests, forexample by oral and/or intravenous dosing of a compound to awarm-blooded mammal using standard techniques.

The following results were obtained on a standard in-vitro test system.The activity is described in terms of the minimum inhibitoryconcentration (MIC) determined by the agar-dilution technique with aninoculum size of 10⁴ CFU/spot. Typically, compounds are active in therange 0.01 to 256 μg/ml.

Staphylococci were tested on agar, using an inoculum of 10⁴ CFU/spot andan incubation temperature of 37° C. for 24 hours—standard testconditions for the expression of methicillin resistance.

Streptococci and enterococci were tested on agar supplemented with 5%defibrinated horse blood, an inoculum of 10⁴ CFU/spot and an incubationtemperature of 37° C. in an atmosphere of 5% carbon dioxide for 48hours—blood is required for the growth of some of the test organisms.Fastidious Gram negative organisms were tested in Mueller-Hinton broth,supplemented with hemin and NAD, grown aerobically for 24 hours at 37°C., and with an innoculum of 5×10⁴ CFU/well.

For example, the following results were obtained for the compound ofExample 1: Organism MIC (μg/ml) Staphylococcus aureus: MSQS 0.125 MRQR0.25 Streptococcus pneumoniae 0.125 Streptococcus pyogenes 0.125Haemophilus influenzae 2 Moraxella catarrhalis 0.5MSQS = methicillin sensitive and quinolone sensitiveMRQR = methicillin resistant and quinolone resistant

Certain intermediates and/or Reference Examples described hereinafterwithin the scope of the invention may also possess useful activity, andare provided as a further feature of the invention.

The invention is now illustrated but not limited by the followingExamples in which unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and    work-up procedures were carried out after removal of residual solids    by filtration;-   (ii) operations were carried out at ambient temperature, that is    typically in the range 18-26° C. and without exclusion of air unless    otherwise stated, or unless the skilled person would otherwise work    under an inert atmosphere;-   (iii) column chromatography (by the flash procedure) was used to    purify compounds and was performed on Merck Kieselgel silica    (Art. 9385) unless otherwise stated;-   (iv) yields are given for illustration only and are not necessarily    the maximum attainable;-   (v) the structure of the end-products of the invention were    generally confirmed by NMR and mass spectral techniques [proton    magnetic resonance spectra were generally determined in DMSO-d₆    unless otherwise stated using a Varian Gemini 2000 spectrometer    operating at a field strength of 300 MHz, or a Bruker AM250    spectrometer operating at a field strength of 250 MHz; chemical    shifts are reported in parts per million downfield from    tetramethysilane as an internal standard (δ scale) and peak    multiplicities are shown thus: s, singlet; d, doublet; AB or dd,    doublet of doublets; dt, doublet of triplets; dm, doublet of    multiplets; t, triplet, m, multiplet; br, broad; fast-atom    bombardment (FAB) mass spectral data were generally obtained using a    Platform spectrometer (supplied by Micromass) run in electrospray    and, where appropriate, either positive ion data or negative ion    data were collected];-   (vi) each intermediate was purified to the standard required for the    subsequent stage and was characterised in sufficient detail to    confirm that the assigned structure was correct; purity was assessed    by HPLC, TLC, or NMR and identity was determined by infra-red    spectroscopy (IR), mass spectroscopy or NMR spectroscopy as    appropriate;-   (vii) in which the following abbreviations may be used:

DMF is N,N-dimethylformamide; DMA is N,N-dimethylacetamide; TLC is thinlayer chromatography; HPLC is high pressure liquid chromatography; MPLCis medium pressure liquid chromatography; DMSO is dimethylsulfoxide;CDCl₃ is deuterated chloroform; MS is mass spectroscopy; ESP iselectrospray; EI is electron impact; CI is chemical ionisation; EtOAc isethyl acetate; MeOH is methanol.

Each of the following Examples comprises an independent aspect of theinvention.

EXAMPLE 1(5R)-3-(3-Fluoro-4-(5-cyano-1,3,4-thiadiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

A mixture of(5R)-3-(3-fluoro-4-(trimethylstannyl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(442 mg, 1.0 mmol), 5-chloro-1,3,4-thiadiazole-2-carbonitrile (151 mg,1.0 mmol), and triphenylarsine (32 mg, 0.1 mmol) inN-methyl-2-pyrrolidinone (5 ml) under an atmosphere of nitrogen wastreated with tris(dibenzylideneacetone)dipalladium(0) (48 mg, 0.05 mmol)and then stirred under an atmosphere of nitrogen for 14 hours at 75° C.The solvent was removed under reduced pressure. A solution of theinvolatile dark oily residue in ethyl acetate (10 ml) was treated withan aqueous solution of potassium fluoride (2M; 10 ml). The mixture wasvortexed for two minutes and then stirred for 15 minutes. The mixturewas extracted with ethyl acetate (150 ml) and the extract was dried(MgSO₄). The dried extract was filtered, the filtrate was concentratedunder reduced pressure, and the residue was purified by chromatographyon silica gel (20 g) (dichloromethane to 2% methanol in dichloromethanegradient) to give the desired product (199 mg). MS (ESP) 372.06 (MH⁺)for C₁₅H₁₀FN₇O₂S. ¹H-NMR (DMSO-d₆) δ: 3.93 (dd, 1H); 4.27 (t, 1H); 4.86(d, 2H); 5.16 (m, 1H); 7.27 (dd, 1H); 7.44 (m, 1H); 6.98 (t, 1H); 7.78(s, 1H); 8.16 (s, 1H).

The intermediate for this compound was prepared as follows:(5R)-5-Azidomethyl-3-(3-fluoro-4-iodophenyl)-13-oxazolidin-2-one

Methanesulfonyl chloride (17.9 ml) was added dropwise to a stirredsolution of(5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-1,3-oxazolidin-2-one(55.8 g) and triethylamine (46.1 ml) in dry dichloromethane (800 ml)under an atmosphere of dry nitrogen and maintained below roomtemperature by an ice-bath. The stirred reaction mixture was allowed towarm to room temperature during 3 hours and then washed sequentiallywith water and brine and then dried (Na₂SO₄). Solvent was removed underreduced pressure to give the intermediate mesylate as a yellow solid (68g) that was used without further purification.

A stirred solution in DMF (800 ml) of a mixture of the intermediatemesylate (68 g) and sodium azide (32.3 g) was heated at 75° C.overnight. The mixture was allowed to cool to room temperature, dilutedwith water, and extracted twice with ethyl acetate. The combinedextracts were washed sequentially with water and brine, and then dried(Na₂SO₄). Solvent was removed under reduced pressure to give a yellowoil that was purified by column chromatography on silica-gel. Elutionwith ethyl acetate-hexanes (1:1) gave the product azide as an off-whitesolid (49 g). The product could be further purified by trituration withethyl acetate/hexanes.

¹H-NMR (DMSO-d₆) δ: 3.57-3.64 (dd, 1H); 3.70-3.77 (dd, 1H); 3.81-3.87(dd, 1H); 4.06 (t, 1H); 4.78-4.84 (m, 1H); 7.05-7.09 (ddd, 1H); 7.45(dd, 1H); 7.68-7.74 (dd, 1H).(5R)-3-(3-Fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

A stirred solution in dioxan (300 ml) of a mixture of the(5R)-5-azidomethyl-3-(3-fluoro4-iodophenyl)-1,3-oxazolidin-2-one (30 g)and bicyclo[2.2.1]heptadiene (30 ml) was heated under reflux overnight.The mixture was allowed to cool to room temperature and then evaporatedto dryness under reduced pressure to give a brown solid. The brown solidwas purified by column chromatography on silica-gel. Elution withmethanol:chloroform (98:2 to 95:5) gave the product triazole as a paleyellow solid (20 g). The product could be further purified bytrituration with dichloromethane/hexanes (1:1) to give an off-whitesolid.

¹H-NMR (DMSO-d₆) δ: 3.86-3.92 (dd, 1H); 4.23 (t, 1H); 4.83 (d, 2H);5.11-5.19 (m, 1H); 7.12-7.16 (dd, 1H); 7.47-7.51 (dd, 1H); 7.76 (s, 1H);7.79-7.85 (dd, 1H); 8.16 (s, 1H).(5R)-3-[3-Fluoro-4-(trimethylstannyl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

A mixture of(5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(5.39 g, 13.9 mmol) and hexamethylditin (5 g, 15.3 mmol) in dioxane (50ml) under an atmosphere of nitrogen was treated withdichlorobis(triphenylphoshine)palladium (II) (487 mg, 0.69 mmol) andthen stirred at 90° C. under an atmosphere of nitrogen for 90 minutes.Silica gel (5 g) was added then the solvent removed under reducedpressure. The residual powder was placed on top of a silica gel column(100 g) and eluted (1% methanol in dichloromethane to 2.5% methanol indichloromethane gradient) to give the desired product (4.545 g).

MS (ESP) 423, 425, 427 (MH⁺) for C₁₅H₁₉FN₄O₂Sn. ¹H-NMR (DMSO-d₆) δ: 0.32(s, 9H); 3.90 (dd, 1H); 4.25 (t, 1H); 4.85 (d, 2H); 5.16 (m, 1H); 7.26(dd, 1H); 7.33 (dd, 1H); 7.41 (dd, 1H); 7.78 (s, 1H); 8.18 (s, 1H).

The preparation of 5-chloro-[1,3,4]thiadiazole-2-carbonitrile isdescribed in

-   -   Gadwood, Robert C.; Barbachyn, Michael Robert; Toops, Dana        Scott; Smith, Herman Walden; Vaillancourt, Valerie Ann.        Preparation of azolylpiperazinylphenyloxazolidinones as        antimicrobials. U.S. (1998), 34 pp. CODEN: USXXAM U.S. Pat. No.        5,736,545 A 19980407 CAN 128:270612 AN 1998:219349 CAPLUS    -   Gadwood, Robert C.; Barbachyn, Michael R.; Toops, Dana S.;        Smith, Herman W.; Vaillancourt, Valerie A. Preparation of        3-[4-(4-azolyl-1-piperazinyl)phenyl]oxazolidin-2-ones as        bactericides. PCT Int. Appl. (1997), 79 pp. CODEN: PIXXD2 WO        9730981 A1 19970828 CAN 127:278210 AN 1997:579705 CAPLUS

EXAMPLE 2(5R)-3-(3-Fluoro-4-(5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

A mixture of(5R)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(436 mg, 1.0 mmol), ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate (197mg, 0.9 mmol), and tris(2-furyl)phosphine (24 mg, 0.1 mmol) intetrahydrofuran (5 ml) under an atmosphere of nitrogen was treated withtris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.05 mmol). The mixturewas stirred under an atmosphere of nitrogen for 14 hours at 75° C. Thesolvent was removed under reduced pressure. A solution of the involatiledark oily residue in ethyl acetate (10 ml) was treated with an aqueoussolution of potassium fluoride (2M; 10 ml). The mixture was vortexed fortwo minutes and then stirred for 15 minutes. The mixture was extractedwith ethyl acetate (150 ml) and the extract was dried (MgSO₄). The driedextract was filtered, the filtrate was concentrated under reducedpressure, and the residue was purified by chromatography on silica gel(20 g) (dichloromethane to 2% methanol in dichloromethane gradient) togive the desired product (40 mg).

MS (ESP) 419.09 (MH⁺) for C₁₇H₁₅FN₆O₄S ¹H-NMR (DMSO-d₆) δ: 1.31 (t, 3H);3.93 (dd, 1H); 4.26 (t, 1H); 4.39 (q, 2H); 4.80 (d, 2H); 5.14 (m, 1H);7.50 (dd, 1H); 7.66 (dd, 1H); 7.70 (s, 1H); 8.12 (s, 1H); 8.32 (t, 1H).

The preparation of ethyl 2-chloro-[1,3,4]thiadiazole-5-carboxylate isdescribed in

-   -   Gadwood, Robert C.; Barbachyn, Michael R.; Toops, Dana S.;        Smith, Herman W.; Vaillancourt, Valerie A. Preparation of        3-[4-(4-azolyl-1-piperazinyl)phenyl]oxazolidin-2-ones as        bactericides. PCT Int. Appl. (1997), 79 pp. CODEN: PIXXD2 WO        9730981 A1 19970828 CAN 127:278210 AN 1997:579705 CAPLUS    -   Demaree, Patricia; Doria, Marie Carmen; Muchowski, Joseph M. The        reaction of certain α-diazocarbonyl compounds with thiophosgene        and ethyl chlorodithioformate. Can. J. Chem. (1977), 55(2),        243-50. CODEN: CJCHAG CAN 88:6803 AN 1978:6803 CAPLUS

EXAMPLE 3(5R)-3-(4-(5-(Aminomethyl)-1,3-thiazol-2-yl)-3-fluorophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

A mixture of(5R)-3-(3-fluoro-4-(trimethylstannyl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(425 mg, 1.0 mmol), tert-butyl (2-bromo-1,3-thiazol-5-yl)methylcarbamate(293 mg, 1.0 mmol), copper (I) iodide (38 mg, 0.2 mmol) in DMF (3 ml)under an atmosphere of nitrogen was treated withtetrakis(triphenylphoshine) palladium (0) (56 mg, 0.05 mmol). Themixture was stirred under an atmosphere of nitrogen for 5 hours at 75°C. The reaction mixture was treated with an aqueous solution ofpotassium fluoride (2M; 10 ml). Ethyl acetate (10 ml) was added and themixture was vortexed for 5 minutes. The resulting precipitate wasfiltered off. The filtrate was extracted with ethyl acetate (100 ml) andthe extract was dried (MgSO₄). The dried extract was filtered, thefiltrate was concentrated under reduced pressure, and the residue waspurified by chromatography on silica gel (20 g) (dichloromethane to 10%methanol in dichloromethane gradient) to give a yellow solid. This wasdissolved in trifluoroacetic acid (5 ml) and stirred at room temperaturefor 20 minutes. The trifluoroacetic acid was removed in vacuo and theresidue dissolved in DMSO (3 ml). This was purified by reverse phasechromatography (5% acetonitrile to 95% acetonitrile in water) to givethe desired product (70 mg).

MS (ESP) 375.11 (MH⁺) for C₁₆H₁₅FN₆O₂S ¹H-NMR (DMSO-d₆) δ: 3.95 (dd,1H); 4.28 (t, 1H); 4.39 (q, 2H); 4.84 (d, 2H); 5.18 (m, 1H); 7.45 (dd,1H); 7.63 (dd, 1H); 7.75 (s, 1H); 8.00 (s, 1H); 8.17 (s, 1H); 8.20 (t,1H); 8.26 (s, 2H).

EXAMPLE 4(5R)-3-(3-Fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

A mixture of2-fluoro-N′-acetyl-4-((5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl)benzohydrazide(268 mg, 0.74 mmol), and Lawesson's reagent (597 mg, 1.47 mmol) inanhydrous toluene(5 ml) under an atmosphere of nitrogen was heated underreflux overnight. The solvent was removed under reduced pressure and theresidue was purified by chromatography on C18 silica gel (Gilson HPLC)(dichloromethane to 2% methanol in dichloromethane gradient) to give thedesired product (199 mg).

MS (ESP) 372.06 (MH⁺) for C₁₅H₁₃FN₆O₂S. ¹H-NMR (DMSO-d₆) δ: 2.82 (s,3H); 3.99 (dd, 1H); 4.33 (t, 1H); 4.89 (d, 2H); 5.21 (m, 1H); 7.52 (m,1H); 7.69 (dd, 1H); 7.79 (s, 1H); 8.21 (s, 1H); 8.27 (m, 1H).

The intermediates for this compound was prepared as follows:tert-Butyl2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzoate

tert-Butyl-4-((5R)-5-(azidomethyl)-1,3-oxazolidin-2-on-3-yl)-2-fluorobenzoate(15 g, 44.6 mmol) was dissolved in dioxane (100 ml).Bicyclo[2.2.1]hepta-2,5-diene (12.3 g, 133.8 mmol) was added and themixture was heated under reflux under nitrogen for 18 hours. The solventwas evaporated in vacuo and the residue was redissolved indichloromethane and treated with hexanes to give a precipitate that wasfiltered, washed with ethyl acetate and collected as the desiredproduct. The filtrate was concentrated and subjected to chromatographyon silica gel eluting with 100% ethylacetate to give a further sample ofthe title compound (combined product weight 14.3 g).

MS (ESP) 363.22 (MH⁺) for C₁₇H₁₉FN₄O₄. ¹H-NMR (DMSO-d₆) δ: 1.55 (s, 9H);3.97 (m, 1H); 4.28 (t, 1H); 4.86 (d, 2H); 5.20 (m, 1H); 7.39 (dd, 1H);7.52 (dd, 1H); 7.78 (s, 1H); 7.86 (t, 1H); 8.20 (s, 1H).tert-Butyl4-((5R)-5-(azidomethyl)-1,3-oxazolidin-2-on-3-yl)-2-fluorobenzoate

has been previously described in Gordeev, Mikhail F.; Luehr, Gary W.;Patel, Dinesh V.; Gadwood, Robert C. Preparation ofN-acyl-3-aryl-2-oxooxazolidine-5-methanamines as bactericides. PCT Int.Appl. (2001), 134 pp. CODEN: PIXXD2 WO 0109107 A1 20010208 CAN134:163021 AN 2001:101116 CAPLUS2-Fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzoicacid

tert-Butyl2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzoate(14.2 g, 39.2 mmol) in dichloromethane was treated with 4N HCl indioxane (5 equivalent) at 0° C., the mixture was stirred for 2 hoursduring which it was allowed to warn to room temperature. Solvent wasevaporated under reduced pressure to give the desired product (11.9 g)in a form suitable for use without further purification.

MS (ESP) 307.14 (MH⁺) for C₁₃H₁₁FN₄O₄. ¹H-NMR (DMSO-d₆) δ: 3.97 (m, 1H);4.29 (t, 1H); 4.86 (d, 2H); 5.20 (m, 1H); 7.39 (dd, 1H); 7.51 (dd, 1H);7.78 (s, 1H); 7.90 (t, 1H); 8.20 (s, 1H); 13.11 (s, bd, 1H).N′-Acetyl-2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzohydrazide

A mixture of2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzoicacid (450 mg, 1.47 mmol), HATU (565 mg, 1.49 mmol) anddiisopropylethylamine (285 mg, 2.21 mmol) in dry DMF (5 ml) was stirredat 0° C. for 30 minutes, followed by the addition of acetic acidhydrazide (130.7 mg, 1.76 mmol). The reaction mixture was then warmed upto room temperature and stirred for 2 hours. The mixture was dilutedwith dichloromethane (20 ml), washed with saturated aqueous NaHCO₃ andbrine, dried over anhydrous MgSO₄ and concentrated under reducedpressure. The remaining residue was purified by column chromatography onsilica gel (5% MeOH in dichloromethane) to give the desired product (289mg).

MS (ESP+) 363.16 (MH⁺) for C₁₅H₁₅FN₆O₄. ¹H-NMR (DMSO-d₆) δ: 1.92 (s,3H); 3.96 (dd, 1H); 4.29 (t, 1H); 4.88 (d, 2H); 5.20 (m, 1H); 7.38 (dd,1H); 7.53 (dd, 1H); 7.69 (t, 1H); 7.79 (s, 1H); 8.20 (s, 1H); 9.97 (s,1H); 10.05 (s, 1H).

EXAMPLE 5(5R)-3-(3-Fluoro-4-(4-methyl-1,3-thiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

A mixture of2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzenecarbothioamide(30 mg, 0.094 mmol) and 1-chloroacetone (13 mg, 0.14 mmol) in dry DMFwas stirred at 60° C. overnight. Solvent was removed under reducedpressure and the residue was purified by reverse phase chromatography(Gilson MPLC C18 column, 5% to 95% acetonitrile in H₂O) to give thetitle compound (21 mg).

MS (ESP) 360.25 (MH⁺) for C₁₆H₁₄FN₅O₂S. ¹H-NMR (DMSO-d₆) δ: 2.47 (s,3H); 3.99 (dd, 1H); 4.29 (t, 1H); 4.88 (d, 2H); 5.20 (m, 1H); 7.45 (s,1H); 7.48 (dd, 1H); 7.64 (dd, 1H); 7.79 (s, 1H); 8.20 (s, 1H); 8.21 (m,1H).

The intermediates for this compound were prepared as follows:2-Fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-13-oxazolidin-2-on-3-yl)benzamide

A solution of2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzoicacid (2.5 g, 8.17 mmol) in dry dichloromethane (25 ml) at 0° C. wastreated with oxalyl chloride (1.56 g, 12.26 mmol) along with one drop ofdimethylformaldehyde. The reaction mixture was allowed to warm to roomtemperature and then stirred for one hour. Ammonium hydroxide (10 eq.)was then added and the reaction mixture was stirred overnight. Themixture was diluted with additional dichloromethane (20 ml) and thenhexanes (30 ml) to give a precipitate that was isolated by filtration togive the desired product (1.5 g).

MS (ESP) 306 (MH⁺) for C₁₃H₁₂FN₅O₃. ¹H-NMR (DMSO-d₆) δ: 3.96 (m, 1H);4.29 (t, 1H); 4.86 (d, 2H); 5.20 (m, 1H); 7.34 (m, 1H); 7.49 (dd, 1H);7.60 (s, 2H); 7.74 (t, 1H); 7.78 (s, 1H); 8.20 (s, 1H).2-Fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzenecarbothioamide

A mixture of2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzamide(95 mg, 0.31 mmol) and Lawesson's reagent (126 mg, 0.31 mmol) in drytoluene (1 ml) was sealed in a microwave reaction vessel and thenirradiated in a Smith Microwave reactor at 160° C. for 20 minutes.Solvent was evaporated under reduced pressure and the residue waspurified by reverse phase chromatography (Gilson MPLC; C18 column; 5% to95% acetonitrile in H₂O) to give the title compound (35 mg).

MS (ESP+) 322.24 (MH⁺) for C₁₃H₁₂FN₅O₂S. ¹H-NMR (DMSO-d₆) δ: 3.94 (dd,1H); 4.28 (t, 1H); 4.87 (d, 2H); 5.19 (m, 1H); 7.28 (dd, 1H); 7.45 (dd,1H); 7.71 (t, 1H); 7.78 (s, 1H); 8.19 (s, 1H); 9.48 (s, 1H); 10.10 (s,1H).

EXAMPLE 6(5R)-3-(3-Fluoro-4-(4-(trifluoromethyl)-1,3-thiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

(5R)-3-(3-Fluoro-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(25 mg, 0.058 mmol) in ethanol (3 ml) was heated to 150° C. in a sealedtube for 7 days. The solvent was then evaporated and the residue waspurified by column chromatography (silica gel; 5% MeOH indichloromethane) to give the title compound (14 mg).

MS (ESP) 414.18 (MH⁺) for C₁₆H₁₁F4N5O₂S. ¹H-NMR (DMSO-d₆) δ: 3.99 (dd,1H); 4.29 (t, 1H); 4.88 (d, 2H); 5.20 (m, 1H); 7.45 (dd, 1H); 7.65 (dd,1H); 7.79 (s, 1H); 8.10 (m, 1H); 8.21 (s, 1H); 8.38 (s, 1H).

The intermediate for this compound was prepared as follows:(5R)-3-(3-Fluoro-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1,3-thiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

A mixture of2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzenecarbothioamide(30 mg, 0.094 mmol) and 1-bromo-3,3,3-trifluoroacetone (27 mg, 0.14mmol) in dry DMF was stirred at 60° C. overnight. Solvent was thenevaporated under reduced pressure and the residue was purified byreverse phase chromatography (Gilson MPLC; C18 column, 5% to 95%acetonitrile in H₂O) to give the title compound (32 mg).

MS (ESP) 432.07 (MH⁺) for C₁₆H₁₆F₄N₅O₃S. ¹H-NMR (DMSO-d₆) δ: 3.52 (d,1H); 3.82 (d, 1H); 3.98 (dd, 1H); 4.30 (t, 1H); 4.88 (d, 2H); 5.20 (m,1H); 7.49 (dd, 1H); 7.62 (dd, 1H); 7.79 (s, 1H); 8.01 (t, 1H); 8.21 (s,1H).

EXAMPLE 7(5-(2-Fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)phenyl)-1,3,4-thiadiazol-2-yl)acetonitrile

The title compound was prepared fromN′-(cyanoacetyl)-2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzohydrazideby the method described for Example 4.

MS (ESP+) 386.06 (MH⁺) for C₁₆H₁₂FN₇O₂S. ¹H-NMR (DMSO-d₆) δ: 4.01 (dd,1H); 4.33 (t, 1H); 4.80 (s, 2H); 4.88 (dd, 2H); 5.20 (m, 1H); 7.58 (dd,1H); 7.71 (dd, 1H); 7.79 (s, 1H); 8.20 (s, 1H); 8.30 (t, 1H).

The Intermediate for this Compound was Prepared as Follows:N′-(Cyanoacetyl)-2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzohydrazide

A mixture of2-fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)benzoicacid (450 mg, 1.47 mmol), HATU (671 mg, 1.764 mmol) anddiisopropylethylamine (285 mg, 2.21 mmol) in dry DMF (5 ml) was stirredat 0° C. for 30 minutes and then treated with cyanoacetohydrazide (219mg, 2.21 mmol). The reaction mixture was then warmed up to roomtemperature and stirred for 2 hours. The mixture was diluted withdichloromethane (20 ml), washed with saturated aqueous NaHCO₃ and thenbrine, dried over anhydrous MgSO₄ and evaporated under reduced pressure.The remaining residue was purified by column chromatography on silicagel (5% MeOH in dichloromethane) to give the desired product (300 mg).¹H-NMR (DMSO-d₆) δ: 2.71 (s, 2H); 3.96 (dd, 1H); 4.29 (t, 1H); 4.88 (d,2H); 5.20 (m, 1H); 7.38 (dd, 1H); 7.53 (dd, 1H); 7.69 (t, 1H); 7.79 (s,1H); 8.20 (s, 1H); 10.32 (s, 1H); 10.44 (s, 1H).

1. A compound of the formula (I), or a pharmaceutically acceptable salt,or an in-vivo-hydrolysable ester thereof,

wherein HET is an N-linked 5-membered, fully or partially unsaturatedheterocyclic ring, containing either (i) 1 to 3 further nitrogenheteroatoms or (ii) a further heteroatom selected from O and S togetherwith an optional further nitrogen heteroatom; which ring is optionallysubstituted on a C atom, other than a C atom adjacent to the linking Natom, with an oxo or thioxo group; and/or which ring is optionallysubstituted on any available C atom, other than a C atom adjacent to thelinking N atom, with a substituent Rs wherein; Rs is selected from:(Rsa): halogen, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, amino,(1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkenylamino,(1-4C)alkylcarbonylamino, (1-4C)alkylthiocarbonylamino,(1-4C)alkyl-OCO—NH—, (1-4C)alkyl-NH—CO—NH—, (1-4C)alkyl-NH—CS—NH—,(1-4C)alkyl-SO2-NH—, or (1-4C)alkyl-S(O)q- (wherein q is 0, 1, or 2);(Rsb): (1-4C)alkyl group which is optionally substituted with onesubstituent selected from hydroxy, (1-4C)alkoxy, amino, cyano, azido,(2-4C)alkenyloxy, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl,(1-4C)alkylamino, (2-4C)alkenylamino, (1-4C)alkyl-SO₂—NH—,(1-4C)alkylcarbonylamino, (1-4C)alkylthiocarbonylamino,(1-4C)alkyl-OCO—NH—, (1-4C)alkyl-NH—CO—NH—, (1-4C)alkyl-NH—CS—NH—,(1-4C)alkyl-SO₂—NH—, (1-4C)alkyl-S(O)q- (wherein q is 0, 1, or 2),(3-6C)cycloalkyl, (3-6C)cycloalkenyl, or an N-linked 5-memberedheteroaryl ring, which ring contains either (i) 1 to 3 further nitrogenheteroatoms or (ii) a further heteroatom selected from O and S togetherwith an optional further nitrogen heteroatom; which ring is optionallysubstituted on a carbon atom with an oxo or thioxo group; and/or thering is optionally substituted on a carbon atom with 1 or 2 (1-4C)alkylgroups; and/or on an available nitrogen atom (provided that the ring isnot thereby quaternised) with (1-4C)alkyl; (Rsc1):a fully saturated4-membered monocyclic ring containing 1 or 2 heteroatoms independentlyselected from O, N, and S (optionally oxidised), and linked via a ringnitrogen or carbon atom; (Rsc2): a saturated or unsaturated 5-memberedmonocyclic ring containing 1 heteroatom selected from O, N, and S(optionally oxidised), and linked via a ring nitrogen atom if the ringis not thereby quaternised, or a ring carbon atom; (Rsc3): a saturatedor unsaturated 6- to 8-membered monocyclic ring containing 1 or 2heteroatoms independently selected from O, N, and S (optionallyoxidised), and linked via a ring nitrogen atom if the ring is notthereby quaternised, or a ring carbon atom; wherein said rings in (Rsc1)to (Rsc3) are optionally substituted on an available carbon atom with 1or 2 substituents independently selected from hydroxy, (1-4C)alkoxy,amino, cyano, azido, (2-4C)alkenyloxy, (1-4C)alkylcarbonyl,(1-4C)alkoxycarbonyl, (1-4C)alkylamino, (2-4C)alkenylamino,(1-4C)alkyl-SO₂—NH—, (1-4C)alkylcarbonylamino,(1-4C)alkylthiocarbonylamino, (1-4C)alkyl-OCO—NH—,(1-4C)alkyl-NH—CO—NH—, (1-4C)alkyl-NH—CS—NH—, (1-4C)alkyl-SO₂—NH—,(1-4C)alkyl-S(O)q- (wherein q is 0, 1, or 2), (3-6C)cycloalkyl, or(3-6C)cycloalkenyl; (Rsd): cyano, nitro, azido, formyl,(1-4C)alkylcarbonyl, or (1-4C)alkoxycarbonyl; wherein at each occurrenceof an Rs substituent containing an alkyl, alkenyl, alkynyl, cycloalkyl,or cycloalkenyl moiety in (Rsa), (Rsb) or (Rsc1) to (Rsc3) each suchmoiety is optionally further substituted on an available carbon atomwith one or more substituents independently selected from F, Cl, and Brand/or with one cyano group; and/or which ring is optionally substitutedon an available nitrogen atom (provided that the ring is not therebyquaternised) with (1-4C)alkyl; or HET is an N-linked 6-membereddihydro-heteroaryl ring containing up to three nitrogen heteroatoms intotal (including the linking heteroatom), which ring is substituted on asuitable C atom, other than a C atom adjacent to the linking N atom,with oxo or thioxo and/or which ring is optionally substituted on anyavailable C atom, other than a C atom adjacent to the linking N atom,with one or two substituents Rs, wherein Rs is as hereinbefore defined,and/or on an available nitrogen atom (provided that the ring is notthereby quaternised) with (1-4C)alkyl; and wherein at each occurrence ofalkyl, alkenyl, and cycloalkyl HET substituents, each is optionallysubstituted with one or more substituents independently selected from F,Cl, and Br and/or with one cyano group; Q is selected from Q1 to Q10:

wherein R² and R³ are independently hydrogen or fluoro; A₁ is carbon ornitrogen; B₁ is O or S (or, in Q9 only, NH); X_(q) is O, S, or N-R¹(wherein R¹ is hydrogen, (1-4C)alkyl, or hydroxy-(1-4C)alkyl); and in Q7each A₁ is independently selected from carbon or nitrogen, with amaximum of 2 nitrogen heteroatoms in the 6-membered ring, and Q7 islinked to T via any of the A₁ atoms (when A₁ is carbon), and linked inthe 5-membered ring via the specified carbon atom, or via A₁ when A₁ iscarbon; Q8 and Q10 are linked to T via either of the specified carbonatoms in the 5-membered ring, and linked to the benzo-ring via either ofthe two specified carbon atoms on either side of the linking bond shown;and Q9 is linked via either of the two specified carbon atoms on eitherside of the linking bond shown; T is an optionally substituted C-linked(fully unsaturated) 5-membered heteroaryl ring system containing 1, 2,or 3 heteroatoms selected from O, N, or S, optionally substituted withone or more substituents independently selected from R^(4h), R^(5h), andR^(6h) defined hereinafter; or T is selected from the following groupsof formula (TAa1) to (TAa6) below (wherein AR1, AR2, AR2a, AR2b, AR3,AR3a, AR3b, AR4, AR4a, CY1, and CY2 are defined hereinbelow);

wherein R^(6h) is selected from hydrogen, (1-4C)alkyl,(1-4C)alkoxycarbonyl, (1-4C)alkanoyl, carbamoyl, and cyano; R^(4h) andR^(5h) are independently selected from hydrogen, halo, trifluoromethyl,cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O)_(q)— (q is 0, 1, or 2),(1-4C)alkanoyl, (1-4C)alkoxycarbonyl, benzyloxy-(1-4C)alkyl,(2-4C)alkanoylamino, —CONRcRv, and —NRcRv, wherein any (1-4C)alkyl groupcontained in the preceding values for R^(4h) and R^(5h) is optionallysubstituted with up to three substituents independently selected fromhydroxy (not on C1 of an alkoxy group, and excluding geminaldisubstitution), oxo, trifluoromethyl, cyano, nitro, (1-4C)alkoxy,(2-4C)alkanoyloxy, hydroxyimino, (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)—(q is 0, 1, or 2), (1-4C)alkylSO₂—NRv-, (1-4C)alkoxycarbonyl, —CONRcRv,and —NRcRv (not on C1 of an alkoxy group, and excluding geminaldisubstitution); wherein Rv is hydrogen or (1-4C)alkyl and Rc is ashereinafter defined; R^(4h) and R^(5h) may further be independentlyselected from (1-4C)alkyl {optionally substituted with up to threesubstituents independently selected from hydroxy (excluding geminaldisubstitution), oxo, trifluoromethyl, cyano, nitro, (1-4C)alkoxy,(2-4C)alkanoyloxy, hydroxyimino, (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)—(q is 0, 1, or 2), (1-4C)alkylSO₂—NRv-, (1-4C)alkoxycarbonyl, —CONRcRv,and —NRcRv (excluding geminal disubstitution); wherein Rv is hydrogen or(1-4C)alkyl}; Rc is as hereinafter defined; and any (1-4C)alkyl groupcontained in the immediately preceding optional substituents (whenR^(4h) and R^(5h) are independently (1-4C)alkyl) is itself optionallysubstituted with up to three substituents independently selected fromhydroxy (not on C1 of an alkoxy group, and excluding geminaldisubstitution), oxo, trifluoromethyl, cyano, nitro, (1-4C)alkoxy,(2-4C)alkanoyloxy, hydroxyimino, (1-4C)alkoxyimino, (1-4C)alkylS(O)_(q)—(q is 0, 1, or 2), (1-4C)alkylSO₂—NRv-, (1-4C)alkoxycarbonyl, —CONRcRv,and —NRcRv (not on C1 of an alkoxy group, and excluding geminaldisubstitution); wherein Rv is hydrogen or (1-4C)alkyl, and Rc is ashereinafter defined; or R^(4h) is selected from one of the groups in(TAaa) to (TAac) below, or (where appropriate) one of R^(4h) and R^(5h)is selected from the above list of R^(4h) and R^(5h) values, and theother is selected from one of the groups in (TAaa) to (TAac) below:(TAaa)a group of the formula (TAaa1)

wherein Z⁰ is hydrogen or (1-4C)alkyl; X⁰ and Y⁰ are independentlyselected from hydrogen, (1-4C)alkyl, (1-4C)alkoxycarbonyl, halo, cyano,nitro, (1-4C)alkylS(O)_(q)— (q is 0, 1, or 2), RvRwNSO₂—,trifluoromethyl, pentafluoroethyl, (1-4C)alkanoyl, and —CONRvRw [whereinRv is hydrogen or (1-4C)alkyl; and Rw is hydrogen or (1-4C)alkyl]; orone of X⁰ and Y⁰ is selected from the above list of X⁰ and Y⁰ values,and the other is selected from phenyl, phenylcarbonyl, —S(O)_(q)-phenyl(q is 0, 1, or 2), N-(phenyl)carbamoyl, phenylaminosulfonyl, AR2,(AR2)-CO—, (AR2)-S(O)q- (q is 0, 1, or 2), N-(AR2)carbamoyl, and(AR2)aminosulfonyl; wherein any phenyl group in (TAaa) may be optionallysubstituted with up to three substituents independently selected from(1-4C)alkyl, cyano, trifluoromethyl, nitro, halo, and(1-4C)alkylsulfonyl; (TAab) an acetylene of the formula —≡—H or-≡-(1-4C)alkyl; (TAac) —X¹—Y¹-AR2, —X¹—Y¹-AR2a, —X¹—Y¹-AR2b, —X¹—Y¹-AR3,—X¹—Y¹-AR3a, or —X¹—Y¹-AR3b; wherein X¹ is a direct bond or —CH(OH)— andY¹ is —(CH₂)_(m)—, —(CH₂)_(n)—NH—(CH₂)_(m)—, —CO—(CH₂)_(m)—,—CONH—(CH₂)_(m)—, —C(═S)NH—(CH₂)_(m)—, or —C(═O)O—(CH₂)_(m)—,—(CH₂)_(n)— or —CH(Me)-(CH₂)_(m)— and Y¹ is —(CH₂)_(m)—NH—(CH₂)_(m)—,—CO—(CH₂)_(m)—, —CONH—(CH₂)_(m)—, —C(═S)NH—(CH₂)_(m)—,—C(═O)O—(CH₂)_(m)—, —S(O)_(q)—(CH2)_(m)—, —CH₂O—, —CH₂NH— or—CH₂N((1-4C)alkyl)- and Y¹ is —CO—(CH₂)_(m)—, —CONH—(CH₂)_(m)—, or—C(═S)NH—(CH₂)_(m)—; Y¹ is —SO₂— when X¹ is —CH₂NH— or—CH₂N((1-4C)alkyl)-, and Y¹ is —(CH₂)_(m)— when X¹ is —CH₂O— or—CH₂N((1-4C)alkyl)-; n is 1, 2, or 3; m is 0, 1, 2, or 3 and q is 0, 1,or 2; and when Y¹ is —(CH₂)_(m)—NH—(CH₂)_(m)— each m is independentlyselected from 0, 1, 2, or 3; wherein Rc is selected from groups (Rc 1)to (Rc5): (Rc1) (1-6C)alkyl {optionally substituted with one or more(1-4C)alkanoyl groups (including geminal disubstitution) and/oroptionally monosubstituted with cyano, (1-4C)alkoxy, trifluoromethyl,(1-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR1 definedhereinafter), (1-4C)alkylS(O)_(q)— (q is 0, 1, or 2); or on any but thefirst carbon atom of the (1-6C)alkyl chain, optionally substituted withone or more groups (including geminal disubstitution) each independentlyselected from hydroxy and fluoro, and/or optionally monosubstituted withoxo, —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or(1-4C)alkyl], (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylS(O)_(p)NH—, or(1-4C)alkylS(O)_(p)-((1-4C)alkyl)N— (p is 1 or 2)}; (Rc2) R¹³CO—,R¹³SO₂—, or R¹³CS—; wherein R¹³ is selected from (Rc2a) to (Rc2e) (Rc2a)AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, or CY2; (Rc2b)hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, —NRvRw [wherein Rv ishydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], ethenyl,2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl,2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl,2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl,2-(AR1)ethenyl, 2-(AR2)ethenyl, or 2-(AR2a)ethenyl; (Rc2c) (1-10C)alkyl{optionally substituted with one or more groups (including geminaldisubstitution) each independently selected from hydroxy, (1-10C)alkoxy,(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy,(1-4C)alkanoyl, carboxy, phosphoryl [—O—P(O)(OH)₂, and mono- anddi-(1-4C)alkoxy derivatives thereof], phosphiryl [—O—P(OH)₂ and mono-and di-(1-4C)alkoxy derivatives thereof], and amino; and/or optionallysubstituted with one group selected from phosphonate [phosphono,—P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivatives thereof],phosphinate [—P(OH)₂ and mono- and di-(1-4C)alkoxy derivatives thereof],cyano, halo, trifluoromethyl, (1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkylamino,di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylaminocarbonyl,di((1-4C)alkyl)aminocarbonyl, (1-4C)alkylS(O)_(p)NH—,(1-4C)alkylS(O)_(p)-((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O)_(p)NH—,fluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)N—, (1-4C)alkylS(O)_(q)— [the(1-4C)alkyl group of (1-4C)alkylS(O)_(q)— being optionally substitutedwith one substituent selected from hydroxy, (1-4C)alkoxy,(1-4C)alkanoyl, phosphoryl [—O—P(O)(OH)₂, and mono- and di-(1-4C)alkoxyderivatives thereof], phosphiryl [—O—P(OH)₂ and mono- anddi-(1-4C)alkoxy derivatives thereof], amino, cyano, halo,trifluoromethyl, (1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxycarbonyl,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, carboxy,(1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino,(1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino,(1-4C)alkylaminocarbonyl, di((1-4C)alkyl)aminocarbonyl,(1-4C)alkylS(O)_(p)NH—, (1-4C)alkylS(O)_(p)-((1-4C)alkyl)N—,(1-4C)alkylS(O)_(q)—, AR1-S(O)_(q)—, AR2-S(O)_(q)—, AR3-S(O)_(q)—, andAR2a, AR2b, AR3a, and AR3b versions of AR2 and AR3 containing groups],CY1, CY2, AR1, AR2, or AR3, AR1-O—, AR2-O—, AR3-O—, AR1-S(O)_(q)—,AR2-S(O)_(q)—, AR3-S(O)_(q)—, AR1-NH—, AR2-NH—, AR3-NH— (p is 1 or 2 andq is 0, 1 or 2), and AR2a, AR2b, AR3a, and AR3b versions of AR2 and AR3containing groups}; (Rc2d) R¹⁴C(O)O(1-6C)alkyl wherein R¹⁴ is AR1, AR2,(1-4C)alkylamino (the (1-4C)alkyl group being optionally substitutedwith (1-4C)alkoxycarbonyl, carboxy), benzyloxy-(1-4C)alkyl, or(1-10C)alkyl {optionally substituted as defined for (Rc2c)}; (Rc2e)R¹⁵O— wherein R¹⁵ is benzyl, (1-6C)alkyl {optionally substituted asdefined for (Rc2c)}, CY1, CY2, or AR2b; (Rc3) hydrogen, cyano,2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl,2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl,2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl, 2-(AR1)ethenyl,2-(AR2)ethenyl, or of the formula (Rc3a)

wherein X⁰⁰ is —OR¹⁷, —SR¹⁷, —NHR¹⁷, or —N(R¹⁷)₂; R¹⁷ is hydrogen whenX⁰⁰ is —NHR¹⁷ or —N(R¹⁷)₂, R¹⁷ is (1-4C)alkyl, phenyl, or AR2 when X⁰⁰is —OR¹⁷, —SR¹⁷, or —NHR¹⁷; and R¹⁶ is cyano, nitro,(1-4C)alkylsulfonyl, (4-7C)cycloalkylsulfonyl, phenylsulfonyl,(1-4C)alkanoyl, or (1-4C)alkoxycarbonyl; (Rc4) trityl, AR1, AR2, AR2a,AR2b, AR3, AR3a, or AR3b; (Rc5) RdOC(Re)=CH(C═O)—, RfC(═O)C(═O)—,RgN═C(Rh)C(═O)—, or RiNHC(Rj)=CHC(═O)— wherein Rd is (1-6C)alkyl; Re ishydrogen or (1-6C)alkyl, or Rd and Re together form a (3-4C)alkylenechain; Rf is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl,(1-6C)alkoxy(1-6C)alkyl, —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl;Rw is hydrogen or (1-4C)alkyl], (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy,di-(1-4C)alkylamino(2-6C)alkoxy; Rg is (1-6C)alkyl, hydroxy, or(1-6C)alkoxy; Rh is hydrogen or (1-6C)alkyl; Ri is hydrogen,(1-6C)alkyl, AR1, AR2, AR2a, AR2b; and Rj is hydrogen or (1-6C)alkyl;wherein AR1 is an optionally substituted phenyl or optionallysubstituted naphthyl; AR2 is an optionally substituted 5- or 6-membered,fully unsaturated monocyclic heteroaryl ring containing up to fourheteroatoms independently selected from O, N, and S (but not containingany O—O, O—S or S—S bonds), and linked via a ring carbon atom, or a ringnitrogen atom if the ring is not thereby quaternised; AR2a is apartially hydrogenated version of AR2 linked via a ring carbon atom orlinked via a ring nitrogen atom if the ring is not thereby quaternised;AR2b is a fully hydrogenated version of AR2 linked via a ring carbonatom or linked via a ring nitrogen atom; AR3 is an optionallysubstituted 8-, 9-, or 10-membered, fully unsaturated bicyclicheteroaryl ring containing up to four heteroatoms independently selectedfrom O, N, and S (but not containing any O—O, O—S or S—S bonds), andlinked via a ring carbon atom in either of the rings comprising thebicyclic system; AR3a is a partially hydrogenated version of AR3 linkedvia a ring carbon atom, or linked via a ring nitrogen atom if the ringis not thereby quaternised, in either of the rings comprising thebicyclic system; AR3b is a fully hydrogenated version of AR3, linked viaa ring carbon atom, or linked via a ring nitrogen atom, in either of therings comprising the bicyclic system; AR4 is an optionally substituted13- or 14-membered, fully unsaturated tricyclic heteroaryl ringcontaining up to four heteroatoms independently selected from O, N, andS (but not containing any O—O, O—S or S—S bonds), and linked via a ringcarbon atom in any of the rings comprising the tricyclic system; AR4a isa partially hydrogenated version of AR4, linked via a ring carbon atom,or linked via a ring nitrogen atom if the ring is not therebyquaternised, in any of the rings comprising the tricyclic system; CY1 isan optionally substituted cyclobutyl, cyclopentyl, or cyclohexyl ring;CY2 is an optionally substituted cyclopentenyl or cyclohexenyl ring. 2.A compound of claim 1, or a pharmaceutically acceptable salt, or in-vivohydrolysable ester thereof, wherein Q is selected from Q1, Q2, Q4, Q6,and Q9.
 3. A compound of claim 1, or a pharmaceutically acceptable salt,or in-vivo hydrolysable ester thereof, wherein T is selected from (TAa1)to (TAa6).
 4. A compound of formula (IB), or a pharmaceuticallyacceptable salt, or in-vivo hydrolysable ester thereof,

wherein HET is 1,2,3-triazole, 1,2,4-triazole, or tetrazole, or HET is adihydro version of pyrimidine, pyridazine, pyrazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, or pyridine; R² and R³ are independentlyhydrogen or fluoro; and T is selected from (TAa1 to TAa6).
 5. A compoundof claim 4, or a pharmaceutically acceptable salt, or in-vivohydrolysable ester thereof, wherein HET is 1,2,3-triazole,1,2,4-triazole, or tetrazole; R² and R³ are independently hydrogen orfluoro; and T is selected from (TAa1 and 2).
 6. A compound of theformula (I) as claimed in any preceding claim, or a pharmaceuticallyacceptable salt, or in-vivo hydrolysable ester thereof, wherein Rs isselected from fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, bromomethyl, cyanomethyl, cyano, amino, azido,alkylthioalkyl, and 2-propynyl.
 7. A pharmaceutical composition whichcomprises a compound of claim 1, or a pharmaceutically acceptable saltor an in-vivo hydrolysable ester thereof, and a pharmaceuticallyacceptable diluent or carrier.
 8. A method for producing anantibacterial effect in a warm blooded animal in need of such treatment,which comprises administering to said animal an effective amount of acompound of a compound of claim 1, or a pharmaceutically acceptablesalt, or an in-vivo hydrolysable ester thereof.
 9. A process for themanufacture of a compound of claim 1, comprising one or more of theprocesses (a) to (i) below: (a) modifying a substituent in orintroducing a substituent into another compound of formula (I); (b)reaction of a compound of formula (II):

wherein Y is a displaceable group with a compound of the formula (III):HET  (III) wherein HET is HET-H free-base form or HET-anion formed fromthe free base form; (c) reaction of a compound of the formula (IV):Q-Z  (IV) wherein Z is an isocyanate, amine or urethane group with anepoxide of the formula (V):

(d) reaction of a compound of formula (VI):

wherein Y′ is a group HET as hereinabove defined, X is a replaceablesubstituent located at a position substituted by T in any of thearomatic embodiments Q1-Q8 of Qn as hereinabove defined for Q, but withX in place of the substituent T, with a compound of the formula (VII):T-X′  (VII) wherein T-X′ is a five-membered heterocycle with 1-3heteroatoms drawn in combination from O, N, and S and X′ is areplaceable C-linked substituent; wherein the substituents X and X′ arechosen to be complementary pairs of substituents known in the art to besuitable as complementary substrates for coupling reactions catalysed bytransition metals such as palladium(0); (e) reaction of a compound offormula (VIII):

wherein Y′ is a group HET as defined herein above and X1 and X2 here areindependently optionally substituted heteroatoms drawn in combinationfrom O, N, and S such that C(X1)X2 constitutes a substituent that is acarboxylic acid derivative located at a position substituted by T in anyof the aromatic embodiments Q1-Q10 of Qn as hereinabove defined for Qwith a compound of the formula (IX) and X3 and X4 are independentlyoptionally substituted heteroatoms drawn in combination from O, N, andS:

and one of C(X1)X2 and C(X3)X4 constitutes an optionally substitutedhydrazide, thiohydrazide, or amidrazone, and the other one of C(X1)X2and C(X3)X4 constitutes an optionally substituted acylating,thioacylating, or imidoylating agent such that C(X1)X2 and C(X3)X4 maybe condensed together to form a 5-membered heterocycle containing 3heteroatoms drawn in combination from O, N, and S; (f) reaction of acompound of formula (X):

wherein Y′ is a group HET as defined herein above and C(X5)X6constitutes a substituent located at a position substituted by T in anyof the aromatic embodiments Q1-Q8 of Qn as hereinabove defined for Qwith a compound of the formula (XI):

wherein one of C(X5)X6 and C(X7)X8 constitutes an optionally substitutedalpha-(leaving-group-substituted)ketone, and the other one of C(X5)X6and C(X7)X8 constitutes an optionally substituted amide, thioamide, oramidine, such that C(X5)X6 and C(X7)X8 are groups that may be condensedtogether to form a 5-membered heterocycle containing 2 heteroatoms drawnin combination from O, N, and S, by methods well-known in the art; (g)for HET as optionally substituted 1,2,3-triazoles compounds of formula(I), cycloaddition via the azide to acetylenes, or to acetyleneequivalents; (h) for HET as 4-substituted 1,2,3-triazole compounds offormula (I), reacting aminomethylisoxazolines with 1,1-dihaloketonesulfonylhydrazones; (i) for HET as 4-substituted 1,2,3-triazolecompounds of formula (I), reacting azidomethyl isoxazolines withterminal alkynes using Cu(I) catalysis; and thereafter if necessary: (i)removing any protecting groups; (ii) forming a pharmaceuticallyacceptable salt; or (iii) forming an in-vivo hydrolysable ester.
 10. Acompound selected from(5R)-3-(3-Fluoro-4-(5-cyano-1,3,4-thiadiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;(5R)-3-(3-Fluoro-4-(5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;(5R)-3-(4-(5-(Aminomethyl)-1,3-thiazol-2-yl)-3-fluorophenyl)5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;(5R)-3-(3-Fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;(5R)-3-(3-Fluoro-4-(4-methyl-1,3-thiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;(5R)-3-(3-Fluoro-4-(4-(trifluoromethyl)-1,3-thiazol-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one;and(5-(2-Fluoro-4-((5R)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-on-3-yl)phenyl)-1,3,4-thiadiazol-2-yl)acetonitrile;or a pharmaceutically acceptable salt or an in-vivo hydrolysable esterthereof.